TWI388280B - Facially amphiphilic polyaryl and polyarylalkynyl polymers and oligomers and uses thereof - Google Patents

Description

Amphoteric polyaryl and polyarylkynyl polymers and oligomers and their uses

The present invention relates to methods of using amphoteric polyaryl and polyarylalkynyl polymers and oligomers, including such polymers and oligomers as antimicrobial agents and as hemorrhagic complications associated with heparin medical therapy The medical use of the antidote. The invention also relates to novel amphoteric polyaryl and polyarylalkynyl polymers and oligomers and compositions thereof, including pharmaceutical compositions.

Bacterial resistance is currently a major health problem worldwide. Multiple drug resistance is common in many human pathogens (Hiramatsu, K. et al., J. Antimicrob. Chemother. 40:311-313 (1998); Montecalvo, MA et al. Antimicro. Agents Chemother. 38: 1363-1367 (1994) Butler, JC et al. J. Infect. Dis. 174:986-993 (1996); Lyytikainen, O. et al. J. Hosp. Infect. 31:41-54 (1995)), and anti-drug hospitals The incidence of infections is growing rapidly. For example, in some US hospitals, in-hospital pathogens (such as Lactococcus and Acinetobacter) cause multiple drug determinants and are not actually available for current antimicrobial agents (Threlfall, EJ et al., Lancet 347: 1053-1054 ( 1996); Bradley, JS and Scheld, WM, Clin. Infect. Dis. 24 (Suppl. 2): S213-221 (1997)). Antibacterial properties have now reached contagious proportions and antibiotic treatments due to various abuses, including overuse (Monroe, S. and Polk, R., Curr. Opin. Microbiol. 3:496-501 (2000)), Improper Sub-medical grade administration (Guillemot, D. et al., JAMA 279: 365-370 (1998)) and misuse as an antimicrobial growth promoter in animal blood (Lathers, CM, J. Clin. Pharmacol. 42: 587-600 (2000)). The threat of bioterrorism provides a further impetus for the development of novel antibiotic classes, particularly against antibiotics that do not develop resistant strains. The Medical Science Association's focus on developing new antibiotics should be challenged. However, many of the studies on the synthesis of known drugs, such as cephalosporins and quinolones, although they may be useful in a short period of time, are inevitably encountered in bacterial resistance and become ineffective. Antibacterial drugs currently correspond to about 65% of the world market for anti-infective series: Volume II: The world market for antibacterial medications, Kalorama Information (2003). Thus, medically effective antimicrobials that act on novel mechanisms can provide economic and human health benefits.

After the initial discovery of cecropin and magainin, antimicrobial peptides became a large and growing biologically important class of compounds (Zasloff, M., Curr. Opin. Immunol. 4:3 -7 (1992); Zasloff, M., Trends Pharmacol. Sci. 21:236-238 (2000)). These compounds represent the first line of defense against microorganisms of many species, including plants, insects, silkworms and mammals (Boman, HG, Immunol. Rev. 173:5-16 (2000); Hancock, RE and Lehrer, R., Trends Biotechnol. 16:82-88 (1998)). In mammals, peptides are produced and secreted by the skin, sticky surfaces, and neutrophils. There are many different classes of natural host defensive peptides (Zasloff, M., Curr. Opin. Immunol. 4:3-7 (1992); Zasloff, M., Trends Pharmacol. Sci. 21:236-238 (2000); Steiner, H. et al., Nature, 292: 246-248 (1981); Ganz, T. et al., Eur. J. Haematol. 44: 1-8 (1990); Tang, YQ et al., Science 286: 498 -502 (1999); Ganz, T. et al. J. Clin. Invest. 76: 1427-1435 (1985); Landon. C. et al., Protein Sci. 6: 1878-1884 (1997); Zhao, C Et al. FEBS Lett. 346:285-288 (1994); Peggion, E. et al., Biopolymers (Peptide Science) 43:419-431 (1998); Dempsey, CE, Biochim. Biophys. Acta 1031:143- 161 (1990)), however, typically comprises a majority of 20-40 amino acid residues and adopts an amphoteric secondary structure as shown in FIG.

Although host defense peptides are found in a variety of different species and are composed of many different sequences, their physiochemical properties have significant similarities. They adopt an amphoteric configuration in which one side of the secondary structure is separated by a positively charged group and the hydrophobic group is on the opposite surface. For example, memannine and some other naturally occurring antibacterial peptides include positively charged amino acids and large hydrophobic moments. Although these peptides exhibit relatively high chain length changes, hydrophobic changes, and charge distribution changes, they have a high propensity to adopt an alpha-helical configuration in a hydrophobic environment, for example, a cell surface or a natural or synthetic film (Oren, Z. and Shai, Y., Biopolymers (Peptide Science) 47:451-463 (1998)). The periodic distribution of hydrophobic and hydrophilic side chains in their amino acid sequence allows the separation of hydrophobic and hydrophilic side chains to the opposite of the cylinder formed by the helix. These structures can be described in terms of both faces, regardless of whether the secondary structure is a spiral or a sheet-like fold. In fact, it is responsible for the overall physiochemical properties of the biological activities of these peptides and their inaccurate sequence (Zasloff, M., Curr. Opin. Immunol. 4:3-7 (1992); Zasloff, M., Trends Pharmacol. Sci. 21:236-238 (2000); Hancock, RE and Lehrer, R., Trends Biotechnol. 16:82-88 (1998); DeGrado, WF et al. J. Amer. Chem. Soc. 103: 679-681 (1981); DeGrado, WF, Adv. Prot. Chem. 39: 51-124 (1988); Tossi, A. et al. Biopolymers 55: 4-30 (2000); Merifield, EL et al. J. Pept. Protein Res. 46: 214-220 (1995); Merrifield, RB et al., Proc Natl Acad Sci (USA) 92: 3449-3453 (1995)). Since the overall amphiphilicity (non-special order, secondary structure or palmarity) is preferably interrelated with the antimicrobial activity of these peptides, it appears that any suitable amphoteric substance (not necessarily alpha-helix or beta-sheet) ) can have antimicrobial properties.

The cytotoxic activity of these cationic and amphoteric antimicrobial peptides is also more specific for bacteria than for mammalian cells. This specificity is most likely related to the fundamental difference between the two film types. For example, bacteria have a high proportion of negatively charged phospholipid bases on their surface, but, in contrast, the outer layers of the cell membrane of animal cells are mainly composed of neutral lipids (Zasloff, M., Nature 415:389-395 ( 2002)). The presence of cholesterol in animal cell membranes also appears to reduce the activity of antimicrobial peptides.

The bactericidal activity of the subject defensive peptide occurs very rapidly within minutes of exposing the bacteria to the lethal peptide dose. A number of mechanisms have been proposed for cell killing processes. According to the carpet mechanism, the host defensive peptide aggregates parallel to the surface of the membrane (Gazit, E. et al., Biohemistry 34: 11479-11488 (1995); Pouny, Y. et al., Biochemistry 31: 12416-12423 (1992)), The film is thinned and eventually the film is broken. In a mechanism known as a barrier plate, peptides bound to the cell surface are self-contained in a rotating membrane spiral bundle to form stable aqueous pores in the membrane (Merrifield, RB et al., Ciba Found. Symp. 186:5- 20 (1994)). According to a third possible mechanism (DeGrado, WF et al., Biophys. J. 37: 329-338 (1982)), the peptide initially binds only to the outer layer of the bilayer, as compared to the inner layer of the bilayer, resulting in lateral lateral Surface pressure increases. This unbalanced pressure causes the peptide to shift into the interior of the bilayer while forming a temporary opening in the film. These transient pores allow for the hydration of the polar side chains of the peptide and leakage of cellular contents. Most antimicrobial peptides may function with more than one of these mechanisms. In addition, some peptide classes can interact with intercellular or intracellular targets (Zasloff, M., Trends Pharmacol. Sci. 21:236-238 (2000)).

In addition to fully characterized antibacterial activity, several host defensive peptides have anti-fungal activity. Examples of mammalian, insect and amphibious peptides with proven anti-fungal activity include defensins, antibiotics, lactoferrin-B, cecropin and dermaseptin (DeLucca) , AJ and Walsh, TJ, Antimicob. Agents Chemother. 43:1-11 (1999)). The cytotoxic mechanism appears to have a mechanism similar to that of bacteria, causing a rapid lysis of the mold film.

Several host defense peptides also have antiviral activity. For example, several host defense peptides also inhibit the replication of both DNA and RNA viruses. NP-1, a prototype alpha-defensin protects cells in culture from herpes simplex virus-2 infection. Blockades apparently occur in very early stages of infection because peptides prevent viral entry, but dry staining between viral glycoproteins and cellular heparin sulfate receptors (Sinha, S. et al. Antimicrob. Agents Chemother. 47) :494-500 (2003)). Several other subject defensive peptides have been shown to be resistant to herpes simplex virus-1 (Belaid, A. et al., J. Med. Virol. 66: 229-234 (2002); Egal, M. et al. Antiviral activity of J. Antimicrob. Agents 13:57-60 (1999)) with human cytomegalovirus (Andersen, JH et al. Antiviral Rs. 51:141-149 (2001)). NP-1 also inhibits adenoviral infection in culture (Bastian, A. and Schafer, H., Regul. Pept. 15: 157-161 (2001)).

It has also been demonstrated that human alpha-defensins inhibit the replication of HIV-1 isolates in vitro (Zhang, L. et al. Science 298:995-1000 (2002)) and active components with soluble fractions, Inhibition of HIV-1 replication is secreted from CD8 T lymphocytes isolated from long-term undeveloped AIDS patients (Zhang, L. et al. Science 298:995-1000 (2002)). Unknown defensins inhibit the mechanism of HIV replication, but blockade occurs at or near the entry of the virus in the early infection cycle. It has also been reported that the antimicrobial peptide melittin and the silkworm antibacterial peptide inhibit HIV-A replication and suggest that they are committed to their activity by inhibiting HIV gene expression (Wachinger, M. et al. J. Gen. Virol. 79: 731-740 (1998)).

The antiviral mechanism of the host defense peptide is clearly independent of the direct virucidal activity, which destroys the integrity of the virion, but rather the early stages of the infection cycle during the entry of the virus into the host cell.

The design of non-biological polymers with well-defined secondary and tertiary structures has received considerable attention in the past few years (Gellman, SH, Acc. Chem. Res. 31: 173-180 (1998); Barron, AE And Zuckermann, RN, Curr. Opin. Chem. Biol. 3:681-687 (1999); Stigers, KD et al., Curr. Opin. Chem. Biol., 3:714-723 (1999)). Using these principles, researchers have designed synthetic antimicrobial peptides that are idealized by amphiphilic alpha-helical alignment of the side chains observed in natural host defense peptides, resulting in many effective and selective antimicrobial compounds (Tossi, A. et al., Biopolymers 55: 4-30 (2000); DeGrado, WF, Adv. Protein. Chem. 39: 51-124 (1988); Maloy, WL and Kari, UP, Biopolyerms 37: 105-122 (1995) Zasloff, M., Curr. Opin. Immunol. 4:3-7 (1992); Boman, HG et al., Eur. J. Biochem. 201:23-31 (1991); Oren, Z. and Shai, Y., Biopolymers 47: 451-463 (1998)).

The beta-peptide also provides another assay and further clarifies the pathways necessary to construct the bactericide. The β-peptide adopts an L+2 helix with a geometric repeat of about 3 residues. Therefore, if the polar and non-polar side chains are periodically arranged in the order of the β-peptide with exactly 3 residues, they should be separated to the opposite sides of the helix. DeGrado and co-investigators (Hamuro, Y. et al., J. Amer. Chem. Soc. 121: 12200-12201 (1999); Liu, D. and DeDrado, WF, J. Amer. Chem. Soc., 123 :7553-7559 (2001)) This approach was used to design synthetic beta-peptide oligomers that have approximately equally effective antimicrobial activity against many naturally occurring peptide antibiotics. The antimicrobial activity of these β-peptides and their specificity for bacterial cells beyond mammalian cells can be controlled by fine-tuning their hydrophobicity and chain length. Gellman and co-investigators also synthesized a cyclically bound beta-peptide with potent antimicrobial activity and minimal anti-mammalian cell activity (Porter, E. A. et al. Nature 404: 565 (2000)).

Non-peptide antimicrobial polymers have also been developed. For example, suitably substituted polymers that are capable of taking an amphiphilic configuration and lacking polyamine linkages have been designed and synthesized. The meta-substituted phenylacetylene class has been synthesized using solid phase chemistry techniques, which are folded into a helical structure in a suitable solvent (Nelson, JC et al. Science 277: 1793-1796 (1997); Prince, RB et al. Angew. Chem. Int. Ed. 39:228-231 (2000)). These molecules include an all-hydrocarbon backbone having an ethylene oxide side chain such that upon exposure to a polar solvent (acetonitrile), the backbone is folded to minimize contact with the polar solvent. As a result of the meta substitution, the preferred folded configuration is helical. This spiral fold is attributed to the "solvent" energy relationship, although the importance of favorable π-π aromatic interactions in the folded state may also be of value. Furthermore, addition of the low polar solvent (CHCl ₃₎ to cause a helical structure solved, the folding is reversible proof.

In addition, U.S. Patent No. 6,034,129 to Mandeville et al. discloses an anti-infective vinyl copolymer in which a monomer having a hydrophobic and hydrophilic side chain is randomly polymerized to produce a polymer having amphoteric properties. These materials are produced by the polymerization of hydrophobic and hydrophilic acrylate monomers. Another option is to have the hydrophobic side chain derived from a styrene derivative copolymerized with a hydrophilic acrylate monomer wherein the ionic group is attached to the carboxylic acid.

Tew et al. (Tew, GN et al., Proc. Natl. Acad. Sci. (USA) 99: 5110-5114 (2002)) disclose a series of biomimetic agents (on-surface amphoteric arylamine polymerization with antimicrobial activity). Design and synthesis. The arylamine polymer was designed using recalculated design techniques.

WIPO Publication No. WO 02/100295 discloses amphoteric polyamines, polyesters, polyureas, polycarbonates and methyl urethane polymers having anti-infective activity, as well as these polymerizations having a biocidal surface Object made of matter. The entire disclosure of WIPO Publication No. 02/100295 is incorporated herein by reference.

WIPO Publication No. WO 02/072007 discloses a number of amphoteric polyphenylene and heteroaryl polymers with anti-infective activity, including polyphenylalkynyl polymers, and these polymers with biocidal surfaces Made of objects. WIPO Publication No. 02/072007 is hereby incorporated by reference in its entirety.

The present invention provides methods for using amphoteric polyaryl and polyarylalkynyl polymers and oligomers, including, but not limited to, detoxification as an antimicrobial agent and hemorrhagic complications associated with heparin medical therapy. Pharmaceutical use of polymers and oligomers. The invention also provides novel amphoteric polyaryl and polyarylalkyne polymers and oligomers; and compositions, including pharmaceutical compositions; and methods of using novel polymers and oligomers.

Surface amphoteric polyaryl and polyaryl alkynyl polymers and oligomers of the invention are compounds of formula I: R ¹ -[-A ₁ -s-A ₂ -s] _m -R ² (I) or Accepted salts or solvates wherein R ¹ , R ² , A ₁ , A ₂ , s and m are as defined below. The amphoteric polyaryl and polyarylkynyl oligomers of the invention also include a compound of formula Ia: R ¹ -A ₁ -s-A ₂ -s-A ₁ -R ² (Ia) or an acceptable salt thereof Or a solvate wherein R ¹ , R ² , A ₁ , A ₂ and s are as defined below.

The invention relates to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of formula I, or an acceptable salt thereof or Solvates and pharmaceutically acceptable carriers or diluents. In certain aspects of the invention, the microbial infection is a bacterial infection, a mold infection, or a viral infection.

The invention also relates to a method of killing or inhibiting the growth of a microorganism comprising contacting the microorganism with an effective amount of a polymer or oligomer of formula I, or an acceptable salt or solvate thereof. In certain aspects of the invention, the microorganism is a bacterial cell, a mold or a virus.

The invention further relates to a method of providing an antidote for overdose of low molecular weight heparin in an animal, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of formula I, or Accepted salts or solvates and pharmaceutically acceptable carriers or diluents.

The invention also relates to oligomers of formula Ia, or an acceptable salt or solvate thereof.

The invention further relates to pharmaceutical compositions comprising an Ia oligomer, or an acceptable salt or solvate thereof.

The invention relates to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of formula Ia, or an acceptable salt or solvate thereof, and A pharmaceutically acceptable carrier or diluent. In certain aspects of the invention, the microbial infection is a bacterial infection, a mold infection, or a viral infection.

The invention also relates to a method of killing or inhibiting the growth of a microorganism comprising contacting the microorganism with an effective amount of an oligomer of formula Ia, or an acceptable salt or solvate thereof. In certain aspects of the invention, the microorganism is a bacterial cell, a mold or a virus.

The present invention relates to a method for providing an antidote for overdose of low molecular weight heparin in an animal, the method comprising administering to an animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula Ia, or an acceptable salt thereof or Solvates and pharmaceutically acceptable carriers or diluents.

The present invention provides non-peptide surface amphoteric polyaryl and polyaryl alkynyl polymers and oligomers and methods for using polymers and oligomers in many applications, including their use as antimicrobial agents in medical applications. And the use as an antidote to hemorrhagic complications associated with heparin medical treatment. The present invention also provides novel amphoteric polyaryl and polyarylkynyl polymers and oligomers; and compositions containing novel polymers and oligomers. The invention further provides methods of designing and synthesizing amphoteric polyaryl and polyarylalkyne polymers and oligomers.

Polyaryl and polyarylkynyl polymers of the invention and oligomers of the formula I: R ¹ -[-A ₁ -s-A ₂ -s] _m -R ² (I) or a compound of the formula Ia: R ¹ -A ₁ -s-A ₂ -s-A ₁ -R ² (Ia) or an acceptable salt or solvate thereof, wherein R ¹ , R ² , A ₁ , A ₂ , s and m are as follows definition.

The amphoteric polymers and oligomers on the surface of Formula I and Formula Ia can adopt an amphoteric configuration that allows the polar and non-polar regions of the molecule to separate into different spatial regions.

The amphoteric configuration employed with the polymers and oligomers of the present invention provides a number of uses. For example, the polymers and oligomers of Formula I and Formula Ia are capable of destroying the integrity of the microbial cell membrane, causing microbial growth inhibition or death. Thus, polymers and oligomers have antimicrobial activity, including antibacterial, antifungal, and antiviral activity, and are useful as antimicrobial agents. The polymers and oligomers of Formula I and Formula Ia have a broad range of antimicrobial activity and are effective against a variety of microorganisms, including Gram-positive and Gram-negative bacteria, molds, yeasts, mycobacteria, mycobacteria, protozoa and analog.

The polymers and oligomers of the present invention are useful as antimicrobial agents in a variety of applications. For example, polymers and oligomers of Formula I and Formula Ia (especially oligomers of Formula I and Formula Ia) can be used medically to treat microbial infections in animals, including in humans and non-human vertebrates, such as wild, Taming and farm animals. The animal is administered to an animal in an effective amount of a pharmaceutical composition of Formula I or Formula Ia (especially an oligomer of Formula I or Formula Ia) to treat a microbial infection in the animal. The polymer or oligomer composition can be administered systemically or topically and can be administered to any body location or tissue. Because polymers and oligomers have a broad range of antimicrobial activity, they are useful in the treatment of various infections in animals.

The amphoteric configuration employed by the polymers and oligomers of the present invention forms the basis of another medical use, with polymers and oligomers being used as antidote to hemorrhagic complications associated with heparin medical procedures. Thus, polymers and oligomers of formula I and formula Ia (especially oligomers of formula I or formula Ia) can be used in a method of providing an antidote to overdose of heparin in an animal, the method being in an effective amount The pharmaceutical composition of the polymer or oligomer is administered to the animal.

The polymers and oligomers of the invention may also be used as anti-infective agents or as preservatives. Thus, polymers and oligomers of Formula I and Formula Ia can be used in a method of killing or inhibiting the growth of microorganisms by contacting the microorganism with an effective amount of a polymer or oligomer. For example, polymers and oligomers of Formula I and Formula Ia can be used as anti-resistances in, for example, soaps, hand lotions, paints, smears, polishes, and the like, or in, for example, food, food containers, and food processing appliances. Infective or preservative. The polymer and oligomer are administered as a solution, dispersion or suspension for these purposes. The polymers and oligomers of Formula I and Formula Ia can also be incorporated into plastics that can be molded or shaped into articles, or attached or affixed to a surface to provide a surface-mediated microbicide that kills contact with the surface. Microorganisms or inhibit their growth.

The polymers and oligomers of the present invention were originally designed to mimic the antimicrobial activity of the defensive peptides of the present invention, which may provoke therapeutic agents because of their broad-spectrum activity, rapid bactericidal activity, and development of bacterial resistance. The rate is very low. However, major medical debates have severely hampered the clinical advancement of the use of host defense peptides as a medical agent, including comprehensive toxicity and manufacturing difficulties and costs.

The invention proceeds directly to those medical debates. Many of the oligomers of Formula I and Formula Ia are significantly smaller and easier to prepare than their naturally occurring counterparts. They have the same mechanism of action as megneine (a naturally occurring defensive peptide) and have roughly the same efficacy and the same broad-spectrum effect as melanin. However, the non-peptide polymers and oligomers of the present invention have significantly lower toxicity to human red blood cells, lower preparation costs, and are expected to have higher stability in vivo. Importantly, because these polymers and oligomers mimic the structure and biological activity of the host defensive peptide, the emergence of bacterial resistant strains is highly unlikely. The amphoteric polymers and oligomers of the present invention provide a number of and novel advantages.

The present invention discloses amphoteric polymers and oligomers. The polymer is typically defined as a synthetic compound in a multi-particle size distribution of monomeric subunits of molecular weight and is most often prepared in a one-pot synthesis step. The term "polymer" as used herein refers to a macromolecule comprising a plurality of repeating units or monomers. The term includes homopolymers formed from single type monomers and copolymers formed from two or more different monomers. The monomers may be distributed in the copolymer in a random manner (random copolymer), in an alternating manner (alternating copolymer) or as a block (block copolymer). A polymer or homopolymer of the invention or an alternating copolymer having from about 2 monomer units to about 500 monomer units having from about 300 Daltons to about 1,000,000 Daltons, or from about 400 Dalton to about 120,000 Daltons is the average molecular weight of the range. Preferred polymers are those having from about 5 to about 100 monomer units having an average molecular weight ranging from about 1,000 Daltons to about 25,000 Daltons.

The term "oligomer" as used herein refers to a homogeneous polymer having a defined sequence and molecular weight. The novel solid phase organic chemistry allows the synthesis of uniformly dispersed sequence-specific oligomers (having a molecular weight close to 5,000 Daltons). The oligomers of the polymer have a defined sequence and molecular weight and are often synthesized and purified to homogeneity by either solid phase techniques or stepwise solution chemistry. The oligomers of the invention are those having from about 2 monomer units to about 25 monomer units having oligomers having a molecular weight ranging from about 300 Daltons to about 6,000 Daltons. Preferred oligomers are those having from about 2 monomer units to about 10 monomer units having oligomers having a molecular weight ranging from about 300 Daltons to about 2,500 Daltons.

Oligomers are a preferred class for medical applications because of their defined size and structure. In the case of material applications, polymers in the form of well-defined repeat length distributions are preferred because of their more economical synthesis.

As used herein, the term "polymer backbone", "oligomer backbone" or "backbone" refers to a continuous chain portion of a polymer or oligomer that is included in a monomer upon polymerization. The bond formed between the two. The composition of the polymer or oligomer backbone can be exemplified by the monomers constituting the polymer or oligomer backbone, independent of the composition of the branches or side chains of the polymer or oligomer backbone.

The term "polymer side chain", "oligomer side chain" or "side chain" refers to a monomeric moiety that forms a polymer or oligomer backbone extension after polymerization. In homopolymers and homooligomers, all side chains are derived from the same monomers.

As used herein, "treat", "treated" or "treating" refers to both medical treatment and prophylactic or preventive strategies, wherein the goal is to prevent or reduce (reduce) unwanted. Physiological symptoms, abnormalities or diseases, or obtain favorable or desired clinical results. For the purposes of the present invention, advantageous or desirable clinical outcomes include, but are not limited to, palliative symptoms; reduced symptoms, abnormalities, or disease levels; stable (ie, no worsening) symptoms, abnormalities, or disease states; delayed onset or slowing down Symptoms, abnormalities, or disease progression; improvement of symptoms, abnormalities, or disease states; relief (whether part or all), whether detectable or undetectable, or promotion or improvement of symptoms, abnormalities, or disease. Treatment involves eliciting a clinically important response without undue side effects. Treatment also includes prolonging survival, as compared to the expected survival rate if not treated.

"Animal" terms as used herein include, but are not limited to, human and non-human vertebrates, such as wild, tamed, and farm animals.

The term "microorganism" as used herein includes bacteria, seaweed, mold, yeast, mycoplasma, mycobacteria, parasites, and protozoa.

The terms "antimicrobial," "microbicide," or "biocide" as used herein mean that the polymer, oligomer, or substance so described produces an effect opposite to normal microbial biological function, including in polymerization. The microorganism, when exposed to a substance, oligomer or substance, dies, destroys or prevents the growth or proliferation of microorganisms. This activity may be either bactericidal or bacteriostatic. The term "bactericidal" as used herein refers to killing microorganisms. The term "bacteriogenic" as used herein refers to inhibiting the growth of microorganisms and may be reversible under specific conditions.

The term "amphoteric" as used herein describes a steric structure having separate hydrophobic and hydrophilic regions. Amphoteric polymers must be present in both the hydrophobic and hydrophilic elements along the polymer backbone. The presence of hydrophobic and hydrophilic groups is a necessary condition for the production of amphiphilic molecules, polymers or oligomers, but is not sufficient.

As used herein, "facially amphiphilic" or "facial amphiphilicity" terms describe polymers or oligomers having polar (hydrophilic) and non-polar (hydrophobic) side chains, The configuration (class) that directs the separation of polar and non-polar side chains to the opposite or separate regions of the structure or molecule.

The polyaryl and polyaryl alkynyl polymers and oligomers of the invention are those compounds of formula I: R ¹ -[-A ₁ -s-A ₂ -s-] _m -R ² (I) or acceptable a salt or solvate wherein: A ₁ and A ₂ are independently optionally substituted aryl or optionally substituted heteroaryl, wherein: (i) A ₁ and A _{2 are} independently optionally subjected to one or more polarities ( a PL) group, one or more non-polar (NPL) groups or one or more polar (PL) groups substituted with one or more non-polar (NPL) groups; or (ii) A ₁ or A ₂ One of which is as defined above and optionally via one or more polar (PL) groups, one or more non-polar (NPL) groups or one or more polar (PL) groups and one or more non-polar Substituted by a combination of (NPL) groups; and another group of A ₁ or A ₂ -C≡C(CH ₂ ) _p C≡C-, where p is 0 to 8, and -(CH ₂ ) _p - The alkyl chain system is optionally substituted with one or more amine groups or hydroxyl groups; s is absent or represents -CH ₂ -, -CH ₂ -CH ₂ -, -CH=CH- or -C≡C-; R ¹ (i) hydrogen, polar (PL) or non-polar (NPL) groups and R ² systems - A ₁ -R ¹ , wherein A ₁ is as defined above and is optional Substituted by one or more polar (PL) groups, one or more non-polar (NPL) groups or one or more polar (PL) groups in combination with one or more non-polar (NPL) groups; or (ii a hydrogen, a polar (PL) group or a nonpolar (NPL) group and an R ² system - A ₁ -s-A ₂ -R ¹ , wherein each of A ₁ and A ₂ is as defined above and is optionally subjected to one or Substituting a plurality of polar (PL) groups, one or more non-polar (NPL) groups or one or more polar (PL) groups with one or more non-polar (NPL) groups; or (iii) A' -s- and R ² -A ₁ -s-A', wherein A' is an aryl or heteroaryl group, and either of them is optionally subjected to one or more polar (PL) groups, one or more non-polar Substituting (NPL) or one or more polar (PL) groups with one or more non-polar (NPL) groups; or (iv) A'-s- and R ² systems - A', where A' An aryl or heteroaryl group, optionally in combination with one or more polar (PL) groups, one or more non-polar (NPL) groups, or one or more polar (PL) groups, and one or more Substituted by a combination of non-polar (NPL) groups; or (v) R ¹ and R ² together form a single bond; NPL is independently selected from -B(OR ⁴ ) ₂ or -(NR ^{3 '} ) _{q 1 N P L} - U ^{N P L} - (CH ₂ a non-polar group of _{p N P L} -(NR ^{3 "} ) _{q 2 N P L} -R ⁴ wherein: R ³ , R ^{3 '} and R ^{3 "} are independently selected from the group consisting of hydrogen, alkyl and alkoxy; ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl, wherein any one group is optionally substituted with one or more alkyl or halo groups; U ^{N P L} is absent or Selected from O, S, S(=O), S(=O) ₂ , NR ³ , -C(=O)-, -C(=O)-N=N-NR ³ -, -C(=O )-NR ³ -N=N-, -N=N-NR ³ -, -C(=N-N(R ³ ) ₂ )-, -C(=NR ³ )-, -C(=O)O -, -C(=O)S-, -C(=S)-, -O-P(=O) ₂ O-, -R ³ O-, -R ³ S-, -S-C=N- And -C(=O)-NR ³ -O-, wherein two groups having two chemically unequal terminals may adopt two possible orientations; -(CH ₂ ) _{p N P L} -alkylene chain system Optionally substituted with one or more amine or hydroxyl groups, or the alkyl chain is unsaturated; pNPL is 0 to 8; q1NPL and q2NPL are independently 0 to 2; PL is selected from halo, hydroxyethoxy Methyl, methoxyethoxymethyl, polyoxyethylene and -(NR ^{5 '} ) _{q 1 P L} -U ^{P a} polar group of ^L -(CH ₂ ) _{p P L} -(NR ^{5 "} ) _{q 2 P L} -V, wherein R ⁵ , R ^{5 '} and R ^{5 "} are independently selected from hydrogen, alkyl and alkoxy; U ^{P L} is absent or selected from O, S, S(=O), S(=O) ₂ , NR ⁵ , -C(=O)-, -C(=O)-N=N-NR ⁵ -, -C(=O)-NR ⁵ -N=N-, -N=N-NR ⁵ -, -C(=N-N(R ⁵ ) ₂ )-, -C(=NR ⁵ )-, -C (=O)O-, -C(=O)S-, -C(=S)-, -O-P(=O) ₂ O-, -R ⁵ O-, -R ⁵ S-, -S -C=N- and -C(=O)-NR ⁵ -O-, wherein two groups having two chemically unequal terminals may adopt two possible orientations; the V system is selected from the group consisting of a nitro group, a cyano group, Amino, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , diazonium, hydrazine Amidino, fluorenyl, guanyl, carbaryl, aryl, heterocyclic and heteroaryl, any of which may optionally be subjected to one or more amine, halo, cyano, nitro, Hydroxyl, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , amidino, sulfhydryl, sulfhydryl Yl), aminosulfonyl, aminoalkoxy, aminoalkylthio, lower amidino or benzyloxycarbonyl; -(CH ₂ ) _{p P L} -alkyl chain Substituted by one or more amine or hydroxy groups, or the alkyl chain is unsaturated; pPL is 0 to 8; q1PL and q2PL are independently 0 to 2; and m is 1 to at least about 500; If A ₁ and A ₂ are thiophene, the polar group may not be 3-(propionic acid) or methoxy (diethoxy) ethyl and the non-polar group may not be n-dodecyl; An acceptable carrier or diluent.

Preferably, those polymers and oligomers of formula I wherein A ₁ and A ₂ are independently and optionally substituted o-, m- or p-phenyl are used in the disclosed process. Those oligomers in which the A ₁ and A ₂ systems are optionally substituted with a phenyl group are particularly preferred. It is also preferred that the polymer of the formula I in which one of A ₁ or A ₂ is o-, m- or p-phenyl, and the other heteroaryl group of A ₁ or A ₂ is also preferred. . Preferred heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl and pyridyl base.

An extended or substituted aryl group in which A ₁ and A ₂ are independently and optionally substituted, and (i) one of A ₁ or A ₂ is one or more polar (PL) groups and one Or a plurality of non-polar (NPL) group substitutions, and the other of A ₁ or A ₂ is unsubstituted; or (ii) one of A ₁ or A ₂ is substituted with one or more polar (PL) groups, And one of A ₁ or A ₂ is unsubstituted; or (iii) one of A ₁ or A ₂ is substituted with one or more polar (PL) groups, and the other of A ₁ or A ₂ is One or more non-polar (NPL)-substituted polymers of formula I and oligomers are also preferred. And wherein one of (i) A ₁ or A ₂ is substituted with one or more polar (PL) groups and one or more non-polar (NPL) groups, and the other of A ₁ or A ₂ is unsubstituted; Or (ii) one of A ₁ or A ₂ is substituted with one or more polar (PL) groups, and another unsubstituted polymer and oligomer of A ₁ or A ₂ is especially preferred.

Wherein A ₁ and A ₂ are optionally substituted by a phenyl-phenyl group, wherein one of A ₁ or A ₂ is substituted with one or more polar (PL) groups, and the other of A ₁ or A ₂ is unsubstituted The polymers of formula I and oligomers are preferred. Those polymers and oligomers in which one of A ₁ or A ₂ is substituted with one or two polar groups, and the other of A ₁ or A ₂ is unsubstituted are especially preferred.

In certain aspects of the invention, those polymers and oligomers of formula I in which s is absent are preferred.

In other aspects, it is preferred to use those formula I polymers and oligomers wherein s is -CH=CH- or -C≡C- in the disclosed process. An oligomer of the formula I in which s is -C≡C- is especially preferred.

Wherein (i) R ¹ is hydrogen, a polar (PL) group or a non-polar (NPL) group, and R ² is -A ₁ -R ¹ , wherein A ₁ is as defined above and is optionally subjected to one or more polarities Substituting (PL) groups, one or more non-polar (NPL) groups (classes) or one or more polar (PL) groups with one or more non-polar (NPL) groups; or (ii) A' -s- and R ² -A ₁ -s-A', wherein A' is an aryl or heteroaryl group, and either of them is optionally subjected to one or more polar (PL) groups, one or more non-polar Those polymers of the formula I and oligomers substituted with (NPL) groups or one or more polar (PL) groups in combination with one or more non-polar (NPL) groups are preferred. Those of the formula I oligomer in which R ¹ is hydrogen or a polar (PL) group and R ² is -A ₁ -R ¹ wherein A _{1 is} optionally substituted with one or more polar (PL) groups are more preferred. Those oligomers in which R ¹ is a polar (PL) group (e.g., a halo group) and R ² is a - A _{1 -} R ¹ wherein A _{1 is} optionally substituted with one or more polar (PL) groups are particularly preferred.

In certain aspects of the invention, wherein NPL is -B(OR ⁴ ) ₂ , wherein R ⁴ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl, any of which Those polymers of the formula I and oligomers which are optionally substituted by one or more alkyl or halo groups are preferred.

In other aspects, wherein NPL is -(NR ^{3 '} ) _{q 1 N P L} -U ^{N P L} -(CH ₂ ) _{p N P L} -(NR ^{3 "} ) _{q 2 N P L} -R ⁴ , And R ³ , R ^{3 '} , R ^{3 ′′} , R ⁴ , U ^{N P L} , pNPL, q1NPL and q2NPL are preferably those of the formula I and oligomers as defined above.

Preferably each R ^3, R ^{3 'and} R ^{3 "significance-based} hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy. Especially preferred R ^3, R ^3' and R ^3" Significance Hydrogen.

Preferred R ⁴ meaning a hydrogen-based, C ₁ -C _{1 0} alkyl, C ₃ -C _{1 8} branched alkyl, C ₂ -C _{1 0} alkenyl group, C ₂ -C _{1 0} alkynyl group, C ₃ - C ₈ cycloalkyl, C ₆ -C _{10 0} aryl and heteroaryl, any of which is optionally substituted by one or more C ₁ -C ₆ alkyl or halo groups. Particularly preferred meaning of R ⁴ line C ₁ -C _{1 0} alkyl, C ₃ -C _{1 8} branched alkyl, C ₂ -C _{1 0} alkenyl group, C ₂ -C _{1 0} alkynyl group and a C ₆ -C _{1 0} aryl (especially phenyl).

The preferred U ^{N P L} meanings are O, S, S(=O), S(=O) ₂ , NH, -C(=O)-, -C(=O)-N=N-NH-, -C(=O)-NH-N=N-, -N=N-NH-, -C(=N-N(R ³ ) ₂ )-, -C(=NR ³ )-, -C(= O)O-, -C(=O)S-, -C(=S)-, -O-P(=O) ₂ O-, -R ³ O-, -R ³ S-, -S-C =N- and -C(=O)-NR ³ -O-, wherein the base having two chemically unequal ends can take two possible orientations. Particularly preferred U ^{N P L} means O, NH, -C(=O)-, -C(=O)-N=N-NH-, -C(=O)-NH-N=N-, -N=N-NH-, -C(=N-N(R ³ ) ₂ )-, -C(=NR ³ )-, -C(=O)O-, and -R ³ O-. Preferred polymers and oligomers of formula I also include those compounds in which U ^{N P L} is absent.

In certain aspects of the invention, those polymers and oligomers of formula I wherein U ^{N P L} is -O-P(=O) ₂ O- are preferred.

A preferred pNPL meaning is 0 to 6; a pNPL of 0 to 4 is particularly preferred, and a pNPL of 0 to 2 is most preferred.

Preferred q1NPL and q2NPL are 0 or 1. The meaning of q1NPL and q2NPL from 0 to 1 is particularly preferred, and each q1NPL and q2NPL meaning is optimal at 0.

In the preferred polymers and oligomers of formula I, the alkylene chain in the NPL is unsubstituted or unsaturated.

Polymers of formula I and oligomers of particular significance preferred NPL include C ₁ -C _{1 0} alkoxy, C ₁ -C _{1 0} alkyl group and C ₁ -C _{1 0} alkyl group.

In certain aspects of the invention, it is preferred to use those polymers and oligomers of formula I wherein PL is a halogen group in the disclosed process. Particularly preferred PL means bromo and iodo.

In other aspects of the invention, wherein PL is -(NR ^{5 '} ) _{q 1 P L} -U ^{P L} -(CH ₂ ) _{p P L} -(NR ^{5 "} ) _{q 2 p L} -V, and R ⁵ R ^{5 '} , R ^{5 ′′} , V, U ^{P L} , pPL, q1PL and q2PL are preferably those of the formula I and oligomers as defined above.

Preferably R ^5, R ^{5 'and} R ^{5 "significance-based} hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy. Each R ^5, R ^5' and R ^5" system hydrogen Significance Especially preferred.

The preferred U ^{P L} meanings are O, S, S(=O), S(=O) ₂ , NH, -C(=O)-, -C(=O)-N=N-NH-, - C(=O)-NH-N=N-, -N=N-NH-, -C(=N-N(R ⁵ ) ₂ )-, -C(=NR ⁵ )-, -C(=O O-, -C(=O)S-, -C(=S)-, -O-P(=O) ₂ O-, -R ⁵ O-, -R ⁵ S-, -S-C= N- and -C(=O)-NR ⁵ -O-, wherein the base having two chemically unequal ends can take two possible orientations. Particularly preferred U ^{P L} meanings are O, S, NH, -C(=O)-, -C(=O)-N=N-NH-, -C(=O)-NH-N=N- -N=N-NH-, -C(=N-N(R ⁵ ) ₂ )-, -C(=NR ⁵ )-, -C(=O)O- and -R ⁵ O-. Those polymers of the formula I and oligomers in which U ^{P L} is absent are preferred.

In certain aspects of the invention, those polymers and oligomers of formula I wherein U ^{P L} is -O-P(=O) ₂ O- are preferred.

Preferred V meanings are nitro, cyano, amine, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, C ₁ -C ₆ Alkylamine, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , diazonium, amidino, sulfhydryl, guanyl, carbaryl, semicarbazone, a C ₆ -C _{1 0} aryl group, a heterocyclic ring and a heteroaryl group, wherein any one group is optionally subjected to one or more of an amine group, a halogen group, a cyano group, a nitro group, a hydroxyl group, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , amidino, sulfhydryl, guanyl, aminosulfonyl, aminoalkoxy, lower amidino or benzyloxy Carbonyl substitution.

Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2 , 3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxo Oxazole, pyridine and 2-aminopyridine.

Particularly preferred V is an amine group, a C ₁ -C ₆ alkylamino group, a C ₁ -C ₆ dialkylamino group, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , diazonium, amidino, sulfhydryl, guanyl and carbaryl, any one of which is optionally subjected to one or more of an amine group, a halogen group, a cyano group, a nitro group, a hydroxyl group, NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , amidino, sulfhydryl, guanyl, aminosulfonyl, aminoalkoxy, low carbon Substituted by a mercaptoamino group or a benzyloxycarbonyl group.

Even better V-based amine groups, C ₁ -C ₆ alkylamino groups, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , diazonium, sulfhydryl and anthracene Any one of which is optionally subjected to one or more of an amine group, a halogen group, a cyano group, a nitro group, a hydroxyl group, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , a fluorenyl group (amidino), guanyl, sulfhydryl or aminoalkoxy substituted. A preferred pPL meaning is 0 to 6, and is particularly preferred with a pPL of 0 to 4, and a pPL of 0 to 2 is particularly preferred.

Preferred q1PL and q2PL are 0 or 1. It is particularly preferable to use q1PL and q2PL of 0 or 1, and each of q1PL and q2PL is preferably 0.

In a preferred polymer of the formula I and an oligomer, the alkylene chain in the PL is optionally substituted with one or more amine groups or hydroxyl groups.

Those polymers of the formula I in which m is from 1 to about 500 are preferred. Those polymers of formula I wherein m is from 1 to about 100 or wherein m is from 1 to about 50 are especially preferred.

Those oligomers of formula I wherein m is from 1 to about 25 are preferred; those oligomers wherein m is from 1 to about 20, or wherein m is from 1 to about 10 or wherein m is from 1 to about 5, are preferred. . Those of the formula I oligomers in which m is 1, 2 or 3 are especially preferred.

In certain aspects of the invention, preferred polymers and oligomers of formula I are those wherein: A ₁ and A ₂ are independently optionally substituted ortho-, meta- or para-phenyl, wherein: One of A ₁ and A ₂ is substituted with one or more polar (PL) groups and one or more non-polar (NPL) groups, while the other of A ₁ and A ₂ is unsubstituted; or (ii One of A ₁ and A ₂ is substituted by one or more polar (PL) groups, and the other of A ₁ and A ₂ is unsubstituted; or (iii) one of A ₁ and A ₂ Substituted by one or more polar (PL) groups, and the other of A ₁ and A ₂ is substituted with one or more non-polar (NPL) groups; or s is -C≡C-; R ¹ is (i) Hydrogen, polar (PL) or non-polar (NPL) groups and R ² -A ₁ -R ¹ , wherein A ₁ is as defined above and is optionally subjected to one or more polar (PL) groups, one or more Substituting a non-polar (NPL) group or one or more polar (PL) groups with one or more non-polar (NPL) groups; or (ii) A'-s- and R ² systems - A ₁ - s-A', wherein A' is an aryl or heteroaryl group, and either of them is optionally subjected to one or more polar (PL) groups, one or more non-polar (NPL) groups, or one or more Polar (PL) group substituted with one or more combinations of non-polar (NPL) group and the; an NPL Department ^{_{- (NR 3 ') q 1}} N P L -U N P L - (CH 2) p N P L - ( NR ^{3 ′′} _{q 2 N P L} —R ⁴ , wherein: R ³ , R ^{3 '} and R ^{3 ′} are independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; R ⁴ is selected from hydrogen, C ₁ -C _{1 0} alkyl, C ₃ -C _{1 8} branched alkyl, C ₂ -C _{1 0} alkenyl group, C ₂ -C _{1 0} alkynyl group, C ₃ -C ₈ cycloalkyl a C ₆ -C _{1 0} aryl group and a heteroaryl group, wherein any one group is optionally substituted by one or more C ₁ -C ₆ alkyl groups or a halogen group; U ^{N P L} is absent or selected from O, S, S(=O), S(=O) ₂ , NH, -C(=O)-, -C(=O)-N=N-NH-, -C(=O)-NH-N=N- , -N=N-NH-, -C(=N-N(R ³ ) ₂ )-, -C(=NR ³ )-, -C(=O)O-, -C(=O)S- , -C(=S)-, -O-P(=O) ₂ O-, -R ³ O-, -R ³ S-, -S-C=N- and -C(=O)-NR ³ -O-, wherein two groups of chemically unequal ends may take two possible orientations; the alkyl chain -(CH ₂ ) _{p N P L} - is optionally subjected to one or more amine groups or hydroxyl Substituted; 0 based pNPL to 6; q1NPL and q2NPL independently 0 or 1; PL based halo or ^{_{- (NR 5 ') q 1}} P L -U P L - (CH 2) p P L - (NR 5 ") _{q 2 P L} -V, wherein R ⁵ , R ^{5 '} and R ^{5 ′} are independently selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; U ^{P L} is absent or selected from O , S, S(=O), S(=O) ₂ , NH, -C(=O)-, -C(=O)-N=N-NH-, -C(=O)-NH-N =N-, -N=N-NH-, -C(=N-N(R ⁵ ) ₂ )-, -C(=NR ⁵ )-, -C(=O)O-, -C(=O )S-, -C(=S)-, -O-P(=O) ₂ O-, -R ⁵ O-, -R ⁵ S-, -S-C=N- and -C(=O) -NR ⁵ -O-, wherein two chemically unequal terminal groups can take two possible orientations; V is selected from the group consisting of nitro, cyano, amine, hydroxyl, C ₁ -C ₆ alkoxy Base, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) _2, diazo group, amidino (amidino), guanidino, amidino (guanyl), semicarbazone, C ₆ -C _{1 0} aryl, heterocyclic aryl and heteroaryl, wherein any arbitrary group by a Or more amino, halo, cyano, nitro, _{hydroxyl, -NH (CH 2) p NH} 2, -N (CH 2 CH 2 NH 2) 2, amidino (amidino), guanidino, amidino (guanyl), aminosulfonyl, aminoalkoxy, aminoalkylthio, lower amidino or benzyloxycarbonyl; alkyl chain-(CH ₂ ) _{p P L} - Optionally substituted with one or more amine or hydroxyl groups; pPL is 0 to 6; q1PL and q2PL are independently 0 or 1; and m is 1 to about 5.

The polyaryl and polyarylkynyl oligomers of the present invention also include oligomers of formula I: R ¹ -A ₁ -s-A ₂ -s-A ₁ -R ² (Ia) or an acceptable salt thereof or a solvate wherein: A ₁ and A ₂ are independently optionally substituted aryl or optionally substituted heteroaryl, wherein: (i) A ₁ and A _{2 are} independently optionally subjected to one or more polar (PL) groups. Substituting one or more non-polar (NPL) groups or one or more polar (PL) groups with one or more non-polar (NPL) groups; or (ii) one of A ₁ or A ₂ As defined above and optionally via one or more polar (PL) groups, one or more non-polar (NPL) groups or one or more polar (PL) groups (classes) and one or more non-polar ( Substituted by a combination of NPL), and another base of A ₁ and A ₂ -C≡C(CH ₂ ) _p C≡C-, wherein p is 0 to 8, and -(CH ₂ ) _p -alkylene The base chain is optionally substituted with one or more amine groups or hydroxyl groups; s is absent or is -CH=CH- or -C≡C-; R ¹ is hydrogen, polar (PL) group, non-polar (NPL) group Or -s-A', wherein A is an aryl or heteroaryl group, and either of them is optionally subjected to one or more polar (PL) groups, one or more non-polar Substituting (NPL) or one or more polar (PL) groups with one or more non-polar (NPL) groups; or R ^{2 for} R ¹ ; NPL is independently selected from -B(OR ⁴ ) ₂ or -(NR ^{3 '} ) _{q 1 N P L} -U ^{N P L} -(CH ₂ ) _{p N P L} -(NR ^{3 "} ) _{q 2 N P L} -R ⁴ apolar group, wherein: R ³ , R ^{3 '} and R ^{3 '} are independently selected from the group consisting of hydrogen, alkyl and alkoxy; R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl, any of which Optionally substituted with one or more alkyl or halo; U ^{N P L} is absent or selected from O, S, S(=O), S(=O) ₂ , NR ³ , -C(=O)-, -C(=O)-N=N-NR ³ -, -C(=O)-NR ³ -N=N-, -N=N-NR ³ -, -C(=N-N(R ³ ) ₂ )-, -C(=NR ³ )-, -C(=O)O-, -C(=O)S-, -C(=S)-, -O-P(=O) ₂ O- ^{, -R 3 O -, - R} 3 S -, - S-C = N- , and ^{-C (= O) -NR 3 -O-} , wherein the two unequal terminal chemical groups may take two of the possible bit; alkylene chain _{- (CH 2) p N p} L - system optionally substituted by one or more amino or hydroxy groups, alkoxy or the extension The chain is unsaturated; pNPL is 0 to 8; q1NPL and q2NPL are independently 0 to 2; PL is selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene and -( NR ^{5 '} ) _{q 1 P L} -U ^{P L} -(CH ₂ ) _{p P L} -(NR ^{5 ′} ) _{q 2 P L} -V polar group, wherein R ⁵ , R ^{5 '} and R ^{5 ′} are independently selected From hydrogen, alkyl and alkoxy; U ^{P L} is absent or selected from O, S, S(=O), S(=O) ₂ , NR ⁵ , -C(=O)-, -C(= O)-N=N-NR ⁵ -, -C(=O)-NR ⁵ -N=N-, -N=N-NR ⁵ -, -C(=N-N(R ⁵ ) ₂ )-, -C(=NR ⁵ )-, -C(=O)O-, -C(=O)S-, -C(=S)-, -O-P(=O) ₂ O-, -R ⁵ O-, -R ⁵ S-, -S-C=N- and -C(=O)-NR ⁵ -O-, wherein two chemically unequal terminal groups can take two possible orientations ; V is selected from the group consisting of nitro, cyano, amine, hydroxy, alkoxy, alkylthio, alkylamino, dialkylamino, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , diazonium, amidino, guanyl, guanyl, carbaryl, aryl, heterocyclic and hetero An aryl group, any one of which is optionally subjected to one or more of an amine group, a halogen group, a cyano group, a nitro group, a hydroxyl group, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , 脒Amidino, sulfhydryl, guanyl, aminosulfonyl, aminoalkoxy, aminoalkylthio, lower amidino or benzyloxycarbonyl; alkyl chain -(CH ₂ ) _{p P L} - is optionally substituted by one or more amine groups or hydroxyl groups, or the alkyl chain is unsaturated; pPL is 0 to 8; q1PL and q2PL are independently 0 to 2; A prerequisite is that if A ₁ and A ₂ are thiophenes, the polar group may not be 3-(propionic acid) or methoxy (diethoxy)ethyl and the non-polar group may not be n-dodecyl.

Preferred oligomers falling within the scope of the present invention group include those wherein A ₁ and A ₂ of the system independently optionally substituted o -, m - or p - phenylene of Formula Ia oligomer. It is especially preferred to use an oligomer of the formula Ia in which the A ₁ and A ₂ systems are optionally substituted with a phenyl group. It is also preferred to use an oligomer of the formula Ia in which one of A ₁ or A ₂ is o-, m- or p-phenyl, and the other heteroaryl group of A ₁ or A ₂ . Preferred heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl and pyridyl base.

Those oligomers of the formula Ia in which the A ₁ and A ₂ systems are optionally substituted between the phenyl groups are particularly preferred.

Preferred oligomers of formula Ia include wherein one of A ₁ or A ₂ is substituted with one or more polar (PL) groups and with one or more non-polar (NPL) groups, while A ₁ or A ₂ An unsubstituted oligomer. Preferred oligomers also include those in which one of A ₁ or A ₂ is substituted with one or more polar (PL) groups, and the other of A ₁ or A ₂ is unsubstituted.

Preferred oligomers include those wherein s-C≡C-.

Preferred groups of oligomers having formula Ia include oligomers wherein R ¹ is hydrogen, polar (PL) or non-polar (NPL) groups, and R ² is R ¹ .

Particularly preferred are oligomers of formula Ia wherein R ¹ is selected from the group consisting of hydrogen, halo, nitro, cyano, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl and benzyloxycarbonyl good. Oligomers of the formula Ia in which R ¹ and R ² are halo are especially preferred.

Preferred oligomers falling within the scope of Formula Ia include the NPL-(NR ^{3 '} ) _{q 1 N P L} -U ^{N P L} -(CH ₂ ) _{p N P L} -(NR ^{3 ′} ) _{q 2 N P L} -R ⁴ , and R ³ , R ^{3 '} , R ^{3 ′′} , R ⁴ , U ^{N P L} , pNPL, q1NPL and q2NPL are those oligomers as defined above. Those oligomers in which q1NPL and q2NPL are independently 0 or 1 are preferred.

Preferred R ³ , R ^{3 '} and R ^{3 '} groups include hydrogen and C ₁ -C ₄ alkyl. Those oligomers of formula Ia in which R ³ , R ^{3 '} and R ^{3 '} are each hydrogen are especially preferred. .

Preferred R ⁴ groups include hydrogen, C ₁ -C _{1 0} alkyl, C ₃ -C _{1 8} branched alkyl, C ₂ -C _{1 0} alkenyl group, C ₂ -C _{1 0} alkynyl group, C ₃ - C ₈ cycloalkyl, C ₆ -C _{10 0} aryl and heteroaryl, any of which is optionally substituted by one or more C ₁ -C ₆ alkyl or halo groups. Wherein R ⁴ to line C ₁ -C _{1 0} alkyl, C ₃ -C _{1 8} branched alkyl, C ₂ -C _{1 0} alkenyl group, C ₂ -C _{1 0} alkynyl group or a C ₆ -C _{1 0} aryl Base oligomers are especially preferred. In which R ^{4 'type} hydrogen, C ₁ -C _{1 0} alkyl and C ₃ -C _{1 8} branched alkyl, wherein any group optionally substituted by one or more C ₁ -C ₄ alkyl groups or halo Oligomers are especially preferred.

Wherein U ^{N P L} is O, S, S(=O), S(=O) ₂ , NH, -C(=O)-, -C(=O)-N=N-NH-, -C (=O)-NH-N=N-, -N=N-NH-, -C(=N-N(R ³ ) ₂ )-, -C(=NR ³ )-, -C(=O) O-, -C(=O)S-, -C(=S)-, -O-P(=O) ₂ O-, -R ³ O-, -R ³ S-, -S-C=N - or -C(=O)-NR ³ -O-, wherein those having two chemically unequal terminal groups may take the two possible possible orientations of the oligomer of formula Ia. An oligomer of the formula Ia in which U ^{N P L} is O, S or -(C=O)- is especially preferred. Oligomers of formula Ia in which U ^{N P L} is absent are also preferred.

Those oligomers in which NPL is n-pentyloxy, n-butoxy, second butoxy, tert-butoxy, propoxy, ethoxy, methoxy or phenoxy are preferred.

Those oligomers of the formula Ia in which one or more PL-based halo groups, especially bromo or iodo groups, are preferred.

Preferred oligomers falling within the scope of Formula Ia also include the PL-(NR ^{5 '} ) _{q 1 P L} -U ^{P L} -(CH ₂ ) _{p P L} -(NR ^{5 ′} ) _{q 2 P L} - V, and R ⁵ , R ^{5 '} , R ^{5 ′′} , V, U ^{P L} , pPL, q1PL and q2PL are preferably those oligos as defined above.

Preferably R ^5, R ^{5 'and} R ^{5 "significance-based} hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy. Each R ^5, R ^5' and R ^5", meaning lines to Hydrogen is especially preferred.

The preferred U ^{P L} meanings are O, S, S(=O), S(=O) ₂ , NH, -C(=O)-, -C(=O)-N=N-NH-, - C(=O)-NH-N=N-, -N=N-NH-, -C(=N-N(R ⁵ ) ₂ )-, -C(=NR ⁵ )-, -C(=O O-, -C(=O)S-, -C(=S)-, -O-P(=O) ₂ O-, -R ⁵ O-, -R ⁵ S-, -S-C= N- and -C(=O)-NR ⁵ -O-, wherein the base having two chemically unequal ends can take two possible orientations. Oligomers of formula Ia in which U ^{P L} is absent are also preferred. Preferably, the oligomer of formula Ia wherein U ^{P L} is O, S, -C(=O)-, -C(=O)-O-, -C(=O)-S- or absent. Those oligomers in which U ^{P L-} (C=O)- or are absent are particularly preferred.

In certain aspects of the invention, those polymers and oligomers of formula Ia wherein U ^{P L} is -O-P(=O) ₂ O- are preferred.

Those oligomers of the formula Ia in which q1PL and q2PL are independently 0 or 1 are preferred.

Wherein V is a nitro group, a cyano group, an amine group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, a C ₁ -C ₆ alkylamino group, a C ₁ -C ₆ dialkylamine , -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , diazonium, amidino, sulfhydryl, guanyl, carbaryl, heterocycle Or a heteroaryl group, wherein any one of the groups is optionally subjected to one or more of an amine group, a halogen group, a cyano group, a nitro group, a hydroxyl group, -NH(CH ₂ ) ₂ NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ Those oligomers of the formula Ia which are substituted with amidino, guanyl, anthracene or aminoalkoxy groups are preferred. Particularly preferred V meanings include amine groups, C ₁ -C ₆ alkylamino groups, C ₁ -C ₆ dialkylamino groups, -NH(CH ₂ ) _p NH ₂ , -N(CH ₂ CH ₂ NH ₂ ) ₂ , diazonium, amidino, sulfhydryl or guanyl, any of which is optionally subjected to one or more amine groups, halo groups, -NH(CH ₂ ) _p NH ₂ , -N ( CH ₂ CH ₂ NH ₂ ) ₂ , amidino, guanyl, hydrazine or aminoalkoxy.

Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2 , 3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxo Oxazole, pyridine or 2-aminopyridine.

Particularly preferred oligomers include PL-based halo, fluorenylmethyl, decylethyl, decylpropyl, aminomethyl, aminoethyl, aminopropyl, aminoethylamine carbonyl or amine groups. Those oligomers of methylamine carbonyl.

Those oligomers of the formula Ia in which pPL systems 0 to 4 are preferred are preferred. Those oligomers in which pPL is 0 to 2 are particularly preferred.

Examples of the structure of the oligomer of the formula Ia within the scope of the present invention include the following: Or a physiologically acceptable salt thereof.

In certain aspects, the invention relates to oligomers of formula Ia and compositions comprising oligomers of formula Ia. Compositions of the oligomers of Formula Ia include, but are not limited to, pharmaceutical compositions comprising Ia oligomers and pharmaceutically acceptable carriers or diluents.

In certain aspects of the invention, the polymers and oligomers of Formula I or Formula Ia are referred to as derivatives of prodrugs. The term "prodrug" means a derivative of a drug known to act directly, which has a more enhanced delivery profile and medical value than a drug and is converted to an active drug by an enzyme or chemical method.

When any of the variants occurs more than once in any constituent or in Formula I or Formula Ia, its definition in each case is based on its definition in every other case. Compositions of substituents and/or variants are also permissible only if such compositions will result in a stable compound.

The invention accordingly comprises stereoisomers, diastereomers and optical isomers of formula I or formula Ia and mixtures thereof for use in the treatment of microbial infections in animals, killing or inhibiting the growth of microorganisms and providing low molecular weight heparin. Use of an antidote for overdose. Furthermore, it is of course within the scope of the invention to have stereoisomers, diastereomers and optical isomers of the formula I or formula Ia and mixtures thereof. Mixtures illustrated by non-limiting examples may be racemates or mixtures may contain unequal ratios of one more specific stereoisomer than others. Thus, in certain aspects of the invention, polymers and oligomers of the invention are provided as racemic mixtures. Furthermore, polymers and oligomers of formula I and formula Ia which are substantially pure stereoisomers, diastereomers and optical isomers can be provided. Thus, in certain aspects of the invention, polymers and oligomers are provided which are substantially pure stereoisomers, diastereomers or optical isomers.

In another aspect of the invention, polymers and oligomers of formula I and formula Ia of the formula I and formula Ia may be provided in an acceptable salt form (i.e., in a pharmaceutically acceptable salt) for use in treating microbial infections, killing microorganisms in animals Or inhibit the growth and provide an antidote to the low molecular weight heparin in excess. The polymer or oligomer salt may be used for pharmaceutical purposes or as an intermediate in the form of a medically desirable polymer or oligomer. A polymer or oligomer salt that is considered acceptable is a hydrochloride acid addition salt. When the pharmaceutically active agent has an amine group which can be protonated, the hydrochloride acid addition salt is often an acceptable salt. Because the polymers or oligomers of the present invention can be polyionic, such as polyamines, acceptable polymeric or oligomeric salts in the form of poly(amine hydrochloride) can be provided.

The following terms have the following meanings unless otherwise defined.

The term "alkyl" as used herein by itself or as part of another group refers to both straight and branched chain radicals from 1 to 12 carbons, such as methyl, ethyl, propyl, Isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl Base, fluorenyl, fluorenyl, undecyl, dodecyl.

The term "alkenyl" as used herein, refers to a straight or branched chain of 2 to 20 carbon atoms, excluding the chain lengths that are limited thereby, including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. The alkenyl chain is preferably from 2 to 10 carbon atoms in length, more preferably from 2 to 8 carbon atoms in length, and most preferably from 2 to 4 carbon atoms in length.

As used herein, the term "alkynyl" refers to a straight or branched chain of 2 to 20 carbon atoms, excluding the chain length subject to this limitation, wherein at least one of the reference bonds is between two carbon atoms in the chain. It includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl and the like. The alkynyl chain is preferably from 2 to 10 carbon atoms in length, more preferably from 2 to 8 carbon atoms in length, and most preferably from 2 to 4 carbon atoms in length.

The term "alkylene" as used herein, refers to an alkyl linkage, i.e., an alkyl group, that attaches one radical in the molecule to another.

The term "alkoxy" as used herein denotes a straight or branched chain of 1 to 20 carbon atoms bonded to an oxygen atom, excluding the chain length subject to this limitation, including but not limited to methoxy Base, ethoxy, n-propoxy, isopropoxy and the like. The alkoxy chain is preferably from 1 to 10 carbon atoms in length, more preferably from 1 to 8 carbon atoms in length, even more preferably from 1 to 6 carbon atoms in length.

The term "aryl" as used herein, alone or as part of another radical, refers to a monocyclic or bicyclic aromatic radical, including a carbocyclic ring, comprising from 6 to 12 carbon atoms in the ring moiety. Phenyl, naphthyl or tetrahydronaphthyl.

The term "aryl" may represent a carbocyclic group such as phenyl, naphthyl or tetrahydronaphthyl; and a heterocyclic aryl ("heteroaryl") such as pyridyl, pyrimidinyl, indole Base, furanyl and pyranyl.

The term "strandyl" as used herein by itself or as part of another radical refers to an aryl linkage, i.e., an aryl, which attaches one radical in the molecule to another.

The term "cycloalkyl" as used herein by itself or as part of another group refers to a cycloalkyl group having from 3 to 9 carbon atoms, more preferably from 3 to 8 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.

The term "halogen" or "halo" as used herein by itself or as part of another group refers to chloro, bromo, fluoro or iodo.

As used herein, the term "heteroaryl" refers to having from 5 to 14 ring atoms, sharing 6, 10 or 14 7π-electrons in a ring system array and including carbon atoms and 1, 2 or 3 oxygen, nitrogen. Or the base of a sulfur hetero atom. Examples of heteroaryl groups include thienyl, imidazolyl, oxadiazolyl, isoxazolyl, triazolyl, pyridyl, pyrimidinyl, indole Base, furyl, pyranyl, thiol, pyrazolyl, pyridyl Base, indanyl, isodecyl, isobenzofuranyl, benzoxazolyl, xanthene, 2H-pyrrolyl, pyrrolyl, 3H-indenyl, fluorenyl, carbazolyl, Sulfhydryl, 4H-quine Base, isoquinolyl, quinolyl, anthracene , naphthyridinyl, quinazolinyl, phenanthryl, acridine, pyridinyl, phenanthroline, phenanth Base, isothiazolyl, phenothiazine Base, isoxazolyl, furazanyl and fengan base. Particularly preferred heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1 , 2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4- Oxadiazole, pyridine and 2-aminopyridine.

The term "heteroaryl" as used herein, alone or as part of another radical, refers to a heteroaryl linkage, ie a heteroaryl, which attaches one radical in the molecule to another.

The term "heterocycle" or "heterocyclic ring" as used herein, unless otherwise indicated, refers to a stable 5- to 7-membered mono- or bicyclic or diazepam 7- to 10-membered bicyclic heterocyclic ring. System, any ring may be a saturated or unsaturated ring, and consists of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S, wherein nitrogen and sulfur heteroatoms can be oxidized at random, and The nitrogen heteroatoms are optionally quaternized and include any bicyclic ring group in which any of the above-defined heterocyclic ring is fused to a benzene ring. A ring of 1 oxygen or sulfur comprising 1 oxygen or sulfur, 1 to 3 nitrogen atoms or in combination with 1 or 2 nitrogen atoms is especially useful. The heterocyclic ring can be attached to any heteroatom or carbon atom, resulting in a stable structure. Examples of such heterocyclic groups include hexahydropyridyl and hexahydropyridyl 2-oxyhexahydropyridyl , 2-oxyhexahydropyridyl, 2-oxypyrrolidinyl, 2-oxoazinyl, aziridine, pyrrolyl, 4-hexahydropyridinone, pyrrolidinyl, pyrazolyl, Pyrazolyl, imidazolium, imidazolinyl, imidazolidinyl, pyridyl, pyridyl Base, pyrimidinyl, oxime Base, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, fluorenyl , quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, thiophene A benzothiophenyl group, a thiamorpholinyl group, a thiamorpholinyl anthracene, a thiamorpholinyl anthracene and an oxadiazolyl group. The morpholino is the same as the morpholinyl.

The term "alkylamino" as used herein by itself or as part of another group refers to an amine group substituted with an alkyl group having from 1 to 6 carbon atoms. The term "dialkylamino" as used herein by itself or as part of another group refers to an amine group substituted with two alkyl groups each having from 1 to 6 carbon atoms.

The term "alkylthio" as used herein by itself or as part of another group refers to a thio group substituted with an alkyl group having from 1 to 6 carbon atoms.

The term "lower mercaptoamino group" as used herein by itself or as part of another group refers to an amine group substituted with a C ₁ -C ₆ alkane group.

The term "chemically unequal end groups" refers to functional groups such as esters, decylamines, sulfonamides and N-oxindoles, which are oriented in reversed substituents (eg, -C(=O) O-) produces different chemical entities (eg, -R ¹ C(=O)OR ² -p-R ¹ OC(O=)R ² ).

The amphoteric sex of the present invention has antimicrobial activity and can therefore be used, for example, in a method of treating a microbial infection in an animal.

Accordingly, in certain aspects, the invention relates to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer of formula I as defined above Or an oligomer, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

The invention also relates to a method of treating a microbial infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a polymer or oligomer of formula Ia as defined above, or An acceptable salt or solvate and a pharmaceutically acceptable carrier or diluent.

The use of the polymers and oligomers of the invention to treat microbial infections caused by microorganisms of any type includes, but is not limited to, bacteria, seaweed, mold, yeast, mycobacteria, mycobacteria, parasites, and protozoa. The polymers and oligomers of the invention are therefore effective in the treatment of bacterial, fungal, viral, yeast, mycobacterial, mycobacterial or protozoal infections. In certain aspects of the invention, the microbial infection to be treated is a bacterial infection, a mold infection or a viral infection.

Accordingly, in certain aspects, the present invention relates to a method of treating a bacterial infection, a fungal infection, or a viral infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition, the composition comprising A polymer or oligomer of formula I, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent are defined.

In another aspect, the invention relates to a method of treating a bacterial, fungal or viral infection in an animal in need thereof, the method comprising administering to the animal an effective amount of a pharmaceutical composition, the composition comprising as defined above A polymer or oligomer of Formula Ia, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

The polymer and oligomer of the present invention may be used to kill or inhibit the growth of any of the following microorganisms or the following microorganisms, or alternatively may be administered to treat the local and/or microbial mixture / or whole body microbial infections or diseases: Gram-positive cocci, for example, Staphylococcus (Golden staphylococcus, Staphylococcus epidermidis) and Streptococcus (Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus pyogenes) Gram-negative cocci (eg, gonorrhea and Yersinia pestis) and Gram-negative bacilli, such as Enterobacter (eg, Escherichia coli, Haemophilus), Citrobacter Citrobacter, polymorphic citrate), Salmonella and dysentery and Francis (Dollarram); Gram-negative bacilli, such as Bacillus (Bacillus anthracis, S. Bacteria); more Klebsiella (Klebsiella pneumoniae, K. oxytosus), Enterobacter (Enterobacter aerogenes, Enterobacter cloacae), Hafnia, sand Reptil genus (Serratia marcescens), Proteus (Singular Proteus, Proteus leucocephalum, Proteus vulgaris), Providencia, Yersinia, and Acinetobacter. Moreover, the antimicrobial range of the polymers and oligomers of the present invention encompasses Pseudomonas (Pseudomonas aeruginosa, Pseudomonas maltophilia) and total anaerobic bacteria such as, for example, the genus Pseudomonas, digested Representative of the genus Cocci, Streptococcus pneumoniae and Clostridium; more mycoplasma (M. pneumoniae, Mycoplasma hominis, Urea decomposition mycoplasma) and Mycobacterium, for example, Mycobacterium tuberculosis. This list of microorganisms is for illustrative purposes only and is not to be construed as limiting examples in any way.

Examples of microbial infections or diseases that can be administered to the polymers and oligomers of the present invention include, but are not limited to, human microbial infections or diseases such as, for example, otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, bladder Inflammation, endocarditis, general infection, bronchitis (acute and chronic), septic infection, upper respiratory tract disease, diffuse obstructive pulmonary disease, emphysema, dysentery, enteritis, hepatic ulcer, urethritis , mastitis, parastatitis, gastrointestinal infections, bone and joint infections, fibrocysts, skin infections, wound infections after spinal surgery, abscesses, cellulitis, wound infections, infected burns, burns, infections in the mouth Infection after tooth surgery, osteomyelitis, septic arthritis, cholecystitis, peritonitis with cediitis, biliary tract inflammation, intra-abdominal abscess, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhoid, Meningitis, nervous system infections, salpingitis, endometritis, genital infections, pelvic peritonitis, and eye infections.

Examples of viral infections that can be administered to the polymers and oligomers of the present invention include, but are not limited to, human immunodeficiency virus (HIV-1, HIV-2), hepatitis virus (eg, hepatitis A, hepatitis B). , hepatitis C, hepatitis D and hepatitis E virus), herpes virus (eg, type 1 and type 2 herpes simplex virus, varicella-banded herpes virus, cytomegalovirus, Epstein Barr virus) And human herpesviruses of types 6, 7 and 8); viral infections caused by influenza virus, respiratory syncytial virus (RSV), vaccinia virus and adenovirus. This list is for illustrative purposes only and is not to be construed as limiting examples in any way.

Examples of mold infections which can be administered to the polymers and oligomers of the present invention include, but are not limited to, the genus Bacillus, the genus genus, the genus Rhizoctonia, the oomycetes, the genus, the ascomycetes Mold infection caused by the class and the Basidiomycetes. Mold infections that may be inhibited or treated by the compositions of the polymers and oligomers provided herein include, but are not limited to, for example, any Candida species, including but not limited to, Candida albicans, Candida tropicalis, Candidiasis caused by Candida pink, Candida parapsilosis, Candida albicans, Candida rugosa, and Candida tropicalis, including (but not limited to) onychomycosis, chronic mucocutaneous candidiasis, oral cavity Candidiasis, epiglottis, esophagitis, gastrointestinal infections, genitourinary infections; for example caused by genus Fusarium, including but not limited to, sputum bacillus, scutellaria, black sputum and earthworm Mycosis, including, but not limited to, granulocyte reduction; for example, zygomycetes, such as white mold, cellobacillus, spines, white root mold, cunningamella, Streptomyces caused by the mold, basidobolus and conidobolus, including but not limited to lung, sinus and nasal brain infections; caused by, for example, cryptococcus Hidden ball Diseases, including but not limited to infections of the central nervous system (eg, meningitis) and respiratory tract infections; trichosporonosis caused by, for example, trichosporon beigeli; a pseudofungal fungus caused by a moldy fungus (pseudallescheria boydii); a Fusarium infection caused by, for example, Fusarium, Fusarium solani, Fusarium oxysporum, and Liriomyza sativa; and such as, for example, Penicillium (total subcutaneous abscess), genus Trichophyton (for example, Trichophyton rubrum and Rhizoctonia solani), Helminthosporium (for example, Black bacterium), Helminthosporium, Helminthosporium, Helminthosporium Genus, Paecilomyces lilacinus, Aconitum sclerophylla (skin nodules), Puccinia sphaeroides (folliculitis), Alternaria (skin nodule damage), Aureobasidium pullulans (spleen and disseminated infection), Rhodotorula (spreading infection), Chaetomium (embryo), white ball yeast (mycoplasmosis), Curvularia genus (nasopharyngeal infection), genus Gynostemma (pneumonia), capsular histoplasma, Dermatitis bud, crude cocci, spore Other infections caused by the genus Filaria and Paragonimus globosa and Geotrichum candidum (dispersive infection). It is also possible to use the polymers and oligomers of the invention to kill or inhibit the growth of any of the above listed molds. This list is for illustrative purposes only and is not to be construed as limiting examples in any way.

The polymer or oligomer of any of the above methods can be administered to a human patient. Thus, in certain aspects of the invention, the polymer or oligomer can be administered to a human.

The methods disclosed above also have veterinary applications and can be used to treat a wide variety of non-human vertebrate animals. Thus, in other aspects of the invention, the polymer or oligomer is administered to a non-human vertebrate, such as a wild, tamer, and farm animal, including, but not limited to, cattle, sheep, in any of the above methods. , goats, pigs, dogs, cats and poultry such as chickens, turkeys, quails, pigeons, ornamental birds and the like.

The following are examples of microbial infections that can be treated in a non-human vertebrate by administration of a polymer or oligomer of the invention: pig: intestinal diarrhea, enterovirus, sepsis, dysentery, salmonella, puerperal-free milk-free syndrome, Mastitis; ruminant (bovine, sheep, goat); diarrhea, sepsis, bronchial pneumonia, Salmonella, Pasteurellosis, mycoplasma, genital infection; horse: bronchial pneumonia, joint disease, maternity and postpartum infection , Salmonella; dogs and cats: bronchial pneumonia, diarrhea, dermatitis, otitis media, urinary tract infections, mastitis; poultry (chicken, turkey, donkey, pigeons, ornamental birds and others): mycoplasma, E. coli Infection, chronic respiratory disease, Salmonella, Pasteurellosis, and parrot disease. This list is for illustrative purposes only and is not to be construed as limiting examples in any way.

The polymers and oligomers of the present invention also inhibit the anticoagulant effect of heparin, particularly low molecular weight heparin, and are useful as antidote to hemorrhagic complications associated with low molecular weight heparin medical procedures.

Heparin is commonly used as an anticoagulation and antithrombotic agent in hospital settings. However, there are a number of standard heparin (SH) pharmacokinetic parameters that complicate medical procedures. The high blood stasis protein binding activity of SH hinders subcutaneous administration, and its rapid and unpredictable plasma elimination rate has to be fixed to monitor the activation time of the activated part to evaluate its effectiveness (Turpie, AGG, Am. Heart J. 135: S329-S335 (1998)). Binding to a specific co-coagulation factor (ATIII) at a unique pentasaccharide sequence randomly distributed along the heparin chain is dedicated to the biological activity of SH. A stable ternary complex is then produced by thrombin and factor Xa, causing their inactivation (Kandrotas, R. J. Clin. Pharmacokinet. 22:359-374 (1992)). The inactivation of ATIII/thrombin is caused by the binding of heparin to ATIII via its high affinity pentasaccharide sequence and to thrombin via a contiguous 13 saccharide sequence. Binding of the high affinity pentasaccharide sequence to ATIII only causes inactivation of the ATIII/factor Xa complex. Low molecular weight heparin derivatives (LMWH) have recently become the standard of care for the treatment of major vascular thrombotic conditions (Hirsh, J. and Levine, M. N., Blood. 79: 1-17 (1992)). LMWH is formed by heparin enzymatic or chemical cleavage, which is a potent Factor Xa inhibitor because they include high affinity pentasaccharide sequences. However, they do not include a sufficient amount of additional saccharide units to make the thrombin inhibitor effective (Hhirsh, J. and Levine, M. N., Blood 79: 1-17 (1992)). Thus, LMWH is a more popular antithrombotic agent than standard heparin because they improve the pharmacokinetics and more predictable anticoagulation responses to weight-adjusted doses.

Both SH and LMWH have a high net negative (anionic) charge. Hemorrhagic complications associated with antithrombotic therapy with two agents and overdose can cause severe bleeding. Proteamine can neutralize the heparin effect, due to its positive charge, but protamine medical treatment also has serious opposite side effects, including hypotension, pulmonary hypertension and specific blood cell damage, including platelets and lymphocytes (Wakefield , TW et al., J. Surg. Res. 63:280-286 (1996)). It is important that protamine is not an effective antidote to LMWH (Diness, VO and Ostergaard, PB, Thromb. Haemost. 56:318-322 (1986)), so only supportive strategies can be used to treat hemorrhagic complications from LMWH. The patient until the anticoagulant of the blood is removed. Moreover, the effects of LMWH typically last for 12-24 hours after subcutaneous administration, so the lack of an effective antidote is a serious drawback of its clinical application. The difference in the ability to neutralize the negative clinical effects of SH and LMWH with protamine sulfate is due to differences in the binding affinities of protamine sulfate to SH, LMWH and hemoglobin (Diiness, VO and Ostergaard). , PB, Thromb. Haemost. 56:318-322 (1986)). Therefore, there is a strong need for safe and effective antidote to develop hemorrhagic complications associated with SH and LMWH antithrombotic therapy.

Accordingly, in certain aspects, the present invention relates to a method of providing an antidote for overdose of low molecular weight heparin in an animal, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising a formula as defined above A polymer or oligomer, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

In certain aspects, the invention is also directed to a method of providing an antidote for overdose of low molecular weight heparin in an animal, the method comprising administering to the animal an effective amount of a pharmaceutical composition comprising Formula Ia as defined above A polymer or oligomer, or an acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

In certain aspects of the invention, the polymers and oligomers of the invention are used as anti-infective agents. For example, paints, paints, and adhesives are all exposed to microbial contamination and used where undesirable microbial growth is desired. Thus, the polymers and oligomers of the present invention can be incorporated into polishing agents, paints, sprays or detergents formulated for application to surfaces that inhibit the growth of bacterial species on their surface. These surfaces include, but are not limited to, surfaces such as panels, desks, poles, benches, tables, floors, bedside tables, tools or equipment, door handles, and windows. The polymers and oligomers of the invention can also be incorporated into soaps and hand lotions. The cleaning agents, polishes, paints, sprays, soaps, hand lotions or detergents of the present invention comprise the polymers and oligomers of the present invention which provide their bacteriostatic properties. They may optionally include suitable solvents (types), carriers (classes), thickeners, pigments, perfumes, deodorants, emulsifiers, surfactants, wetting agents, waxes or oils. For example, in certain aspects of the invention, polymers or oligomers are incorporated into formulations for use in pharmaceutically acceptable skin cleansers, particularly for human hand surfaces. Detergents, polishes, paints, sprays, soaps, hand lotions and detergents and the like comprising the antimicrobial polymers and oligomers of the present invention are useful for households and institutions, particularly (but not exclusively) useful Set up for hospitals that prevent nosocomial infections.

In other aspects of the invention, the polymers and oligomers of the invention are used as preservatives and can be used in methods of killing or inhibiting the growth of microorganism species in food. In certain aspects of the invention, the polymer and oligomer are added to the food as a preservative. Foods that may be treated with the polymers or oligomers of the present invention include, but are not limited to, non-acid foods such as mayonnaise or other egg products, potato products, and other vegetable or meat products. In certain aspects, the polymer or oligomer incorporated into the food is part of an edible formulation, optionally including a medium or carrier suitable for convenient mixing or dissolving into a particular food. A medium or carrier which does not interfere with the familiar taste of the favorite food is preferred, such as those known to those skilled in the art of food processing.

In still other aspects of the invention, the polymers and oligomers of the present invention provide a surface-mediated microbicide that kills only surface contact and is used as a surface-mediated anti-infective or preservative.

Any object exposed to or susceptible to bacterial or microbial contamination can be treated with the polymers and oligomers of the present invention to provide a microbial surface. In order to provide a microbial surface, the polymers or oligomers of the invention are attached or coated in a suitable manner, including by covalent bonding, ionic interaction, coulomb interaction, hydrogen bonding or crosslinking. On or in any substrate, including, but not limited to, wood, paper, synthetic polymers (plastics), natural and synthetic fibers, natural and synthetic rubber, cloth, glass, and ceramics. Examples of synthetic polymers include thermosetting or thermoplastic elastomeric polymers, including but not limited to polypropylene, polyethylene, polyvinyl chloride, polyethylene terephthalate, and polymethyl methacrylate. , polyester (such as polylactide, polyglycolide), rubber (such as polyisoprene, polybutadiene or latex), polytetrafluoroethylene, polyfluorene and polyethylene ruthenium polymer or copolymer . Examples of natural rubber include cotton, wool, and linen.

The incidence of pathogenic infections caused by food is of constant concern and allows antimicrobial packaging materials, utensils and surfaces to be of value. The use of antimicrobial instruments, packaging and surfaces is evident in the field of health care and medical equipment. All human or animal health products for internal or external use can hide and transmit pathogens including, but not limited to, surgical gloves, implantable devices, sutures, catheters, dialysis membranes, water filters, and implants.

The polymers and oligomers of the present invention can be incorporated into any of these devices and implants to provide a surface-mediated antimicrobial surface that kills or inhibits the growth of the organism in contact with the surface. For example, in certain aspects of the invention, the polymers and oligomers of the invention are incorporated into woven fibers for use in materials susceptible to bacterial contamination, including but not limited to fabrics, surgical gowns, and carpet. Ophthalmic solutions and contact lenses are also susceptible to contamination and eye infections. The contact lens and the antimicrobial storage container for the cleaning solution incorporating the polymer and oligomer of the present invention can therefore be very valuable.

Accordingly, in certain aspects, the invention relates to a method of killing or inhibiting the growth of a microorganism, the method comprising an effective amount of a polymer or oligomer of formula I as defined above, or an acceptable salt or solvate thereof Contact with microorganisms.

In certain aspects, the invention relates to a method of killing or inhibiting the growth of a microorganism, the method comprising an effective amount of a polymer or oligomer of formula Ia as defined above, or an acceptable salt or solvate thereof, and a microorganism contact.

The polymers and oligomers of the present invention are designed to take an amphoteric configuration that allows the polar and non-polar regions of the molecule to separate into different spatial regions. These configurations include, but are not limited to, repeated secondary structures such as alpha-helix and beta-sheet structures.

For example, in certain aspects of the invention, the polymers of Formula I and Ia are oligomers with oligomers, wherein, for example, one monomer is substituted with both a non-polar and a polar substituent; or a copolymer, wherein, for example, One monomer is substituted with a polar substituent and the other monomer is substituted or unsubstituted with a non-polar substituent. Since the amphoteric properties of the polymer or oligomer are imparted in a periodic side chain pattern rather than in a precise side chain space, it is also expected that the amphoteric polymer and oligomer will be produced by other substitution patterns. And all are covered by the present invention (refer to FIG. 1).

The polymers and oligomers of the present invention are designed using computer-aided computing techniques, such as redesign techniques. The goal of this approach for designing polymers and oligomers is to capture the antimicrobial peptide structure and biological properties within a conventional polymer framework that can be prepared with inexpensive concentration reactions. Thus, the amphoteric system introduces key properties within the polymer and oligomer. The charge density, hydrophobicity, and degree of amphotericity are also important parameters that maximize the lethal activity against microorganisms while minimizing the activity against mammalian cells.

The general approach is as follows: 1) Use molecular dynamics and quantum force field calculations to define a polymer backbone that should be folded into a defined, well-defined stereostructure. The polymer backbone is combined from the repeating units of the monomers. An extensive theoretical study to demonstrate that the polymer is capable of adopting the desired secondary configuration is then completed.

2) Preparation of a model compound (short-chain oligomer) for structural folding analysis by X-ray crystallography.

3) The functional group is then grafted onto the polymer backbone in a computational manner to form a side chain, imparting the desired amphoteric properties of the oligomer or polymer, and maximizing the diversity and maintaining the polymer-like drug. characteristic. The best combination of functional machines is chosen computationally to produce a cationic, amphoteric structure.

4) Synthesis of representative oligomers and polymers used to confirm their structures and measure their biological activity.

5) Completion of biophysical studies to confirm that the polymer binds to the film in the desired configuration and the mechanism of action is as intended by the design.

6) Redesign the structure based on the findings to optimize the potency and selectivity of the compound, and repeat steps 2-4.

The order of monomer repeats in the backbone must conform to the secondary structure taken in the backbone. See, for example, Arnt, L. et al., Polymer Reprints 44: 1266-1267 (2003). The monomer subunit in the main chain is not limited to a monocyclic aryl compound. They may modify the distance between the bases and change the periodicity of the secondary unit to the polycyclic aromatics.

Molecular dynamics and coarse particle modeling programs can be used for the above design approach. See, for example, U.S. Patent Application Serial No. 10/446,171, filed on May 28, 2003, and U.S. Patent Application Serial No. 10/459,698, filed on June 12, 2003. The contents of U.S. Patent Application Serial No. 10/446,171, and U.S. Patent Application Serial No.

Computer-aided calculation techniques for designing polymers and oligomers identify possible low energy configurations with geometric repeats that conform to suitable sequential repeats of less than 7 monomer units. Once these repeated scaffolds are determined and the number of repeats is calculated, polar and non-polar substituents can be incorporated into the monomer to impart molecular amphoteric properties.

High-order basic principle calculations are a technique for determining the low-energy configuration that can enter various oligomers. Although very powerful, unfortunately these techniques have specific limitations (MW limits) known to those skilled in the art. Molecular dynamics simulations are provided to provide alternative techniques that can be effectively applied to the hypothetical molecules of the present invention. A key element in determining the energy of the configuration is the strong electrostatic interaction between adjacent or further monomers (i.e., intermolecular hydrogen bonding) and the rigidity caused by twisting of the backbone or by large functional groups. In order to simulate these interactions in molecular mechanics calculations, the experimental parameters of the representative polymer backbone, the force field, must be determined. Fundamental calculations can be performed on small model compounds using density functional theory (DFT), which shares the basic structural connectivity of the polymer backbone and produces the necessary torsional potential. The steps to accomplish these calculations are: 1. Select a simple model compound that shares a similar twist pattern with the target polymer backbone.

2. Complete geometric optimization of each compound with BLYP/6-31G(d) theoretical values (multiple initial configurations ensure an overall minimum).

3. Calculate the single point energy of the most stable geometric form obtained in step 2 above using B3LYP/6-311G++(dp) or plane wave CPMD.

4. Force the relative torsion to a set angle and repeat steps 2 and 3; 5. Repeat step 4 at several angles; subtract the unbonded interaction to obtain the torsional energy.

6. Fit the cosine series with respect to the torsion angle, which is the force field parameter.

After the computerized determination of the structure and thermodynamic characteristics is compared with the molecules with similar torsion patterns and effective experimental data to prove the applicability of the force field, then the torsion and mode effect of the fit is applied to CHARMM (Brooks, BR, etc.) J. Comp. Chem. 4: 187-217 (1983) and TraPPE (Martin, MG and Siepmann, JI, J. Phys. Chem. B 103: 4508-4517 (1999); Wick, CD et al. J. Phys. Chem. B 104:3093-3104 (2000)) The molecular dynamic field bond stretching, bending, one-four, van der Waals and electrostatic bit combinations. In order to determine the periodic pattern configuration in which the polar and non-polar groups are arranged on opposite sides, the initial configuration can be obtained in the Gaussian package (Frisch, M. et al., 1998 by Gaussian of Pittsburgh, Pennsylvania). Gaussian 98 (A.7 version)). Next, use the parallelized plane wave Car-Parrinello CP-MD (Car, R. and Parrinello, M., Phys. Rev. Lett. 55: 2471-2474 (1985)) program (compare Rothlisberger, U. et al. J. Chem) Phys. 3692-3700 (1996)) Obtains the minimum energy and forced geometry. The polymer configuration without side chains can be studied in the gas phase. The configuration was sampled using both MD and MC methods. The former has an overall motion for the polymer. The latter biasing technique (Siepmann, JI and Frenkel, D., Mol. Phys. 75: 59-70 (1992); Martin, MG and Siepmann, JI, J. Phys. Chem. B 103: 4508-4517 ( 1999); Vlugt, TJ et al., Mol. Phys. 94:727-733 (1998)) allows for efficient acquisition of polymer samples having a number of local low point configurations separated by relatively large energy barriers.

The possible configuration for attaching the side chain base position that would impart the amphoteric properties of the secondary structure is examined. The polymer selected from the gas phase study was further evaluated in the selected interface system mode (n-hexane/water, because its calculation was simple and inexpensive, while fully simulating the liquid/water double layer environment), which has a suitable main chain structure. Type and side chains at the optimal position for introducing the sexes. Repeat the above calculations (also known as variant cellular molecular dynamics or Monte Carlo techniques) with periodic repeats of various symmetrical unit cell series with or without solvent to identify polymers that require interaction between polymers. Level structure. The candidates for synthesis are guided by these calculation results.

A specific embodiment of the invention is a technique for determining the polymer backbone that can produce an amphoteric polymer on the surface by: (1) selecting a region-specifically introduced polar (PL) group and non-polar (NPL) a polymer backbone or scaffold; (2) using a fundamental quantum mechanical calculation to determine the parameters of the molecular mechanics force field; (3) using molecular dynamics or molecular mechanics calculations to calculate the main chain configuration with energy entry; 4) determining the main chain configuration with energy entry, wherein the periodicity of the geometry/configuration repeat conforms to the order repeatability; (5) synthesizing monomers having polar and non-polar substituents; and (6) Or a solid phase synthesis method to synthesize an antimicrobial polymer or oligomer comprising a monomer.

The polyaryl and polyarylalkyne polymers of the present invention are synthesized according to the procedures set forth in WIPO Publ No. 02/072007, the entire disclosure of which is incorporated herein by reference.

The benzynyl polymer can be synthesized by the general method set forth in Scheme 1. In this method, an equal proportion of diacetylenic benzene and a suitable diiodoyl monomer in a toluene/diisopropylethylamine (4:1 ratio), 3 mol% Pd(PPh ₃ ) ₄ And 6 mol% of CuI was placed in a dry flask. The resulting solution was heated at about 70 ° C for about 12 hours. The polymer product was precipitated using a suitable solvent and dried under reduced pressure. Deprotection of the Boc group was accomplished with 4M HCl / dioxane. Refer to Arnt, L. and Tew, GL, J. Am. Chem. Soc. 124:7664-7665 (2002), including support data for experimental procedures and compound characteristics (see page 7665) (available from the Internet http ://pubs.acs.org). The contents of this document are hereby incorporated by reference in its entirety. See also Breitenkamp, RB and Tew, GN, Polymer Reprints 44: 673-674 (2003) and Arnt, L. et al., Polymer Reprints 44: 1266-1267 (2003). The contents of each of these documents are fully incorporated herein by reference.

In certain aspects of the invention, the oligomers of the invention are synthesized in a solid phase synthesis step well known to those skilled in the art. See, for example, Tew et al. (Tew GN et al., Proc. Natl. Sci. USA 99: 5110-5114 (2002)). For example, the benzynyl oligomer of Formula Ia can be synthesized using the solid phase synthesis step using the following Example 1 as an example. See, for example, Barany, G. et al., Int. J. Pept. Prot. Res. 30: 705-739 (1987); Solid-phase Synthesis: A Practical Guide, Kates, SA and Albericio, F., eds., Marcel Dekker, New York (2000); and D Rwald, FZ, Organic Synthesis on Solid Phase: Supports, Linkers, Reactions, 2 ^{n d} Eed., Wiley-VCH, Weinheim (2002).

Those skilled in the art will appreciate that the synthetic methods used to produce the polymers and oligomers of the present invention can be modified to produce different molecular weight ranges. Polymer chemists can readily recognize that the polymer chain length can be varied by techniques known in the art of polymer. The solid phase and solution phase synthesis of the amino acid oligomers is advanced to efficiently produce oligomeric techniques having a uniform order and size, and these techniques can be applied to the present invention.

Thus, the polymers and oligomers of the invention having a molecular weight range can be synthesized. The molecular weight of the polymer and oligomer ranges from about 300 Daltons to about 1,000,000 Daltons. Preferred polymers of the invention have an average molecular weight ranging from about 400 Daltons to about 120,000 Daltons (about 2 to about 500 monomer units). Particularly preferred polymers have an average molecular weight ranging from about 1,000 Daltons to about 25,000 Daltons (about 5 to about 100 monomer units). The oligomers of the invention have a molecular weight ranging from about 300 Daltons to about 6,000 Daltons (about 2 to about 25 monomer units), and preferred oligomers have from about 300 Daltons to about 2,500 channels. The lonton (about 2 to about 10 monomer units) is a molecular weight in the range.

The synthesis of an appropriately substituted amine group is very straightforward. An example of the preparation of a monomer for the meta-phenylene derivative is exemplified by the above Scheme 1. In addition, o- and p-dihalides or Acids are suitable for the precursors of various coupling reactions and have many routes suitable for incorporation into polar and non-polar side chains. The phenolic group on the monomer can be alkylated to give polar and non-polar substituents. Alkylation of commercially available phenols is accomplished by standard Williamson ether synthesis of non-polar side chains with ethyl bromide as the alkylating agent. A polar side chain such as BOC-NH(CH ₂ ) ₂ -Br can be introduced into the bifunctional alkylating agent. Another option is to alkylate the phenol group to introduce the desired polar side chain by using the Mitsonobu reaction with BOC-NH(CH ₂ ) ₂ -OH, triphenylphosphine and diethyl acetylenedicarboxylate. . The art is well known for the necessary methods for synthesizing suitable monomers.

In certain aspects of the invention, the amphoteric polymer and oligomers on the surface disclosed herein provide a surface-mediated microbicide that kills microorganisms in contact with the surface. For these applications, the polymer and oligomer can be attached, coated on almost any substrate or coated in a suitable manner, including covalent bonding, ionic interaction, Coulomb interaction, hydrogen bonding or crosslinking. Including, but not limited to, wood, paper, synthetic polymers (plastics), natural and synthetic fibers, natural or synthetic rubber, cloth, glass and ceramics. The step of attaching, coating and incorporating the polymer of the present invention with an oligomer into a suitable substance or matrix is disclosed in WIPO Publ. WO 02/072007. Suitable matrices and materials are also disclosed in WO 02/072007.

The antimicrobial activity of the polymers and oligomers of the present invention can be tested by methods well known to those skilled in the art. See, for example, Tew G. N. et al., Proc. Natl. Sci. USA 99: 5110-5114 (2002).

Antimicrobial testing is performed according to procedures well known to those skilled in the art. For example, use Escherichia coli or another strain if necessary (such as, for example, Bacillus subtilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Gonococci, Bacillus megaterium, Staphylococcus aureus, Enterococcus faecalis, The micro-diluting technique of Micrococcus yellow or Streptococcus pyogenes completes the antimicrobial test. Other specific bacterial strains that can be screened include Escherichia coli D31 which is resistant to chlorpheniricillin and streptomycin, Streptococcus mutans A436 which is resistant to vancomycin, and Staphylococcus aureus 5332 which is resistant to penicillin. Any polymer or oligomer having activity may be found by purified to homogeneity and re-tested to obtain an accurate IC _{5 0.} Secondary screening includes Klebsiella pneumoniae Kp1, Salmonella typhimurium S5, and Pseudomonas aeruginosa 10 . Traditional micro-media dilution techniques only evaluate single data points between 18-24 hours, but measurements can be extended to 24 hours to monitor cell growth throughout the growth phase. These experiments were performed in LB broth, which is a rich culture medium typically used for cell growth in protein expression, and represents a decisive initial screening of activity. Since salt concentration, protein, and other solutes can affect antibiotic activity, substances that do not exhibit any activity in the rich culture medium can be retested in the minimal medium (M9) to determine whether the rich medium has limited activity. It has been observed that there is no relationship between the culture fluid and the activity, consistent with the mode of action believed to be through a comprehensive film destruction.

A standard assay can be performed to determine if the polymer or oligomer of the present invention is bacteriostatic or bactericidal. Those skilled in the art are familiar with these assays and are performed according to procedures well known to those skilled in the art, for example, by culturing E. coli cells overnight with the polymer or oligomer to be tested and then overlaying the mixture on an agar plate. on. See, for example, Tew GN et al., Proc. Natl. Sci. USA 99:5110-5114 (2002)) and Liu, D. and DeGrado, WF (Liu, D. and DeGrado, WF, J. Amer Chem. Soc. 123) :7553-7559 (2001)).

Those skilled in the art are also familiar with assays for determining the antiviral and antifungal activity of the polymers and oligomers of the present invention. For example, for antiviral assays, see Belaid et al. (Belaid, A. et al., J. Med. Virol. 66: 229-234 (2002)), Egal et al. (Egal, M. et al., Int. J.). Antimicrob. Agents 13:57-60 (1999)), Andersen et al. (Andersen, JH et al. Antiviral Rs 51:141-149 (2001)) and Bastian, A. and Schafer, H. (Bastian, A. and Schafer, H., Regul. Pept. 15:257-161 (2001)). See also Cole, A. M. et al., Proc. Natl. Acad. Sci USA 99: 1813-1818 (2002). For example, for antifungal assays, see Edwards, J. R. et al., Antimicrobial Agents Chemotherapy 33: 215-222 (1989) and Broekaert, W. F. et al., FEMS Microbiol. Lett. 69: 55-60 (1990). The entire contents of each of these documents are fully incorporated herein by reference.

Those skilled in the art are well aware of assays for measuring the cytotoxic selectivity of the polymers and oligomers of the present invention to bacterial and eukaryotic cells. For example, the cytotoxic selectivity is assessed by measuring the hemolytic activity of a polymer or oligomer. To measure the presence of the polymer or oligomer after incubation of human erythrocytes and hemolysis measured values for HC _{5 0} hemolytic activity assay. HC _{5 0} represents a polymer concentration of 50% due to the release of hemoglobin. Reference is made, for example, to Liu, D. and DeGrado, WF (Liu, D. and DeGrado, WF, J. Amer. Chem. Soc. 123:7553-7559 (2001)) and references cited therein. See also Javadpour, MM et al., J. Med. Chem. 39: 3107-3113 (1996).

The vesicle leak assay can be used to confirm that the polymer or oligomer of the present invention interacts with the phospholipid bilayer (a cell membrane mode) and destroys the bilayer. Those skilled in the art are familiar with the vesicle leak assay. Reference is for example made by Tew G. N. et al. (Tew G. N. et al., Proc. Natl. Sci. USA 99: 5110-5114 (2002)) and references cited therein.

Those skilled in the art are well acquainted with assays for determining the heparin neutralization activity of the polymers or oligomers of the present invention, and often use or activate partial thromboplastin time assays (with or without the presence of test compounds) The clotting time of the plasma that delays activation in the presence of a fixed concentration of heparin is measured, or by the factor X assay. See, for example, Kandrotas (Kandrotas, RJ, Clin. Pharmacokinet. 22: 359-374 (1992)), Wakefield et al. (Wakefield, TW et al., J. Surg. Res. 63: 280-286 (1996)) and Diness, V. and Φstergaard, PB (Diness, VO and Φstergaard, PB, Thromb. Haemost. 56:318-322 (1986)) and references cited herein. See also Wong P. C. et al., J. Pharm. Exp. Therap. 292:351-357 (2000) and Ryn-McKenna, J. V. et al., Thromb. Haemost. 63:271-274 (1990).

Polymers and oligomers of the invention for medical applications in any of a number of routes of administration, including but not limited to, oral, buccal, ocular, otic, nasal, topical, parenteral (ie intramuscular) , intraperitoneal, intraperitoneal, subcutaneous, intraspinal, intrathoracic, intravenous and aortic), inhalation, transdermal, intravaginal, transmucosal, transurethral, rectal and transpulmonary.

The polymers and oligomers of the invention are administered in a conventional manner in any path that renders them active. Administration can be by systemic, topical or oral. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal or transocular routes, or intravaginally, by inhalation, with long-acting injections or implants. , but not limited to this. Therefore, the mode of administration of the polymer and oligomer (either alone or in combination with other agents) can be sublingual, injectable (including short-acting, long-acting, implanted, and small pill types for subcutaneous or intramuscular injection). Or use vaginal cream, suppository, pessary, vaginal ring, rectal suppository, intrauterine device and transdermal type, such as patch and cream, but not limited to this.

The particular mode of administration will depend on the indication (eg, whether to administer a microbial infection with a polymer or oligomer or to provide an antidote to hemorrhagic symptoms associated with hepatitis medical practice). The mode of administration may depend on the target pathogen or microorganism. The particular route of administration and choice of dose uptake is adjusted or titrated by the clinician according to methods known to the clinician to facilitate optimal clinical response. The amount of polymer or oligomer to be administered has a medically effective amount. The dosage to be administered will depend on the characteristics of the patient to be treated, for example, the particular animal to be treated, age, weight, health, if there are any simultaneous treatments and frequency of treatment, and can be readily determined by those skilled in the art. (for example, to a clinical staff).

Providing any of several forms of pharmaceutical compositions comprising oligomers of Formula I and Formula Ia, including but not limited to capsules, tablets, lozenges, liquid solutions, liquid emulsions, liquid suspensions, liquid drops, liquid sprays Agents, gels, creams, ointments, dermal patches, powder formulations, and other formulations known in the art.

Thus, a pharmaceutical formulation comprising a polymer and an oligomer and a suitable carrier can be in a solid dosage form including, but not limited to, tablets, capsules, sachets, pellets, pills, powders, and granules; topical dosage forms, It includes, but is not limited to, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels and jellies and foams; and parenteral dosage forms including (but not Limited to this) solutions, suspensions, emulsions and dry powders; which comprise an effective amount of a polymer or oligomer as is customary in the present invention. It is also known in the art that these formulations include active ingredients in combination with pharmaceutically acceptable diluents, fillers, disintegrating agents, binding agents, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifying agents. Agents, buffers, aqueous agents, humectants, solubilizers, preservatives and the like. Dosing devices and methods are known in the art, and the skilled artisan can refer to various pharmacological documents for guidance. For example, you can consult Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman, Sixth Edition, The Pharmaceutical Basis of Therapeutics, MacMilan Publishing Co., New York (1980).

The polymer and oligomer can be formulated for parenteral administration by injection, for example, by rapid injection or continuous infusion. The polymer and oligomer can be administered by subcutaneous continuous infusion over a period of from about 15 minutes to about 24 hours. Formulations for injection in unit dosage form may be presented, for example, in ampoules in which the preservative is added or in a container that is administered multiple times. The composition may take the form of a suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may include formulating agents such as suspending, stabilizing and/or dispersing agents.

Polymers and oligomers for oral administration can be readily formulated by combining these compounds with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, dragees, capsules, gels, syrups, slurries, suspensions and the like which are orally ingested by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and treating into a mixture of granules, and if necessary, adding a suitable adjuvant to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, fillers such as sugars (including but not limited to lactose, sucrose, mannitol, and sorbitol); cellulose formulations such as, but not limited to, corn starch, wheat Starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC) and polyvinylcyclopyridone (PVP). If necessary, a disintegrating agent such as cross-linked polyvinylcyclopyridone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

The dragee core can have a suitable coating. A concentrated sugar solution may be used for this purpose, which may optionally include gum arabic, talc, polyvinylcyclopyridone, carbopol resin, polyethylene glycol, and/or titanium dioxide, natural lacquer solutions, and suitable organics. Solvent or solvent mixture. Dyestuffs or pigments can be added to the tablet or dragee coating to determine or characterize the composition of the different active compound doses.

Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Advancing fabricated capsules may include active ingredients in admixture with a filler such as, for example, lactose, a binder such as, for example, starch, and/or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. . In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should have a dosage suitable for such administration.

The polymer and oligomer compositions for tablet administration may be formulated in a conventional manner such as a tablet or lozenge form.

Polymers and oligomers for administration by inhalation in accordance with the present invention may be conveniently delivered in aerosol form using suitable propellants (eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethylene). Alkane, carbon dioxide or other suitable gas) from a pressurized package or sprayer. In the case of a pressurized aerosol, the unit dose can be determined by a valve that provides a metered value. A powder mixture comprising a compound and a suitable powder base such as lactose or starch may be formulated for use in, for example, a gelatin capsule and a mash in an inhaler or in a syringe.

The polymers and oligomers of the present invention may be formulated into rectal compositions such as suppositories or indwelling enema solutions, for example, including conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the polymers and oligomers can also be formulated into a growth-promoting formulation. These long acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Long-acting injections can be administered at intervals of from about 1 to about 6 months or longer. Thus, for example, the polymer and oligomer can be formulated as a suitable polymer or hydrophobic material (for example, as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, for example, Become a sparingly soluble salt.

The polymer and oligomer of the present invention administered to the skin can be applied, for example, to a medicated cloth, or to a skin medical system which is then supplied to the organism.

The pharmaceutical compositions of the polymers and oligomers of the present invention may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, for example, polyethylene glycol.

The polymer can also be administered in combination with an oligomer with other active ingredients such as, for example, adjuvants, protease inhibitors or other compatible drugs or compounds, wherein the composition must have the desired effect of achieving the desired effect of the methods described herein. Or an advantage (eg, controlling infections caused by harmful microorganisms or treating hemorrhagic complications associated with heparin medical procedures). For example, the polymers and oligomers of the invention can be administered with other antibiotics including, but not limited to, vancomycin, cypro, melapenem, oxicillin, and Mikaxin (amikacin).

With regard to those applications in which the polymers and oligomers of the present invention are used as anti-infectives and/or preservatives, for example, in detergents, polishes, paints, sprays, soaps, hand lotions or detergents, Polymers and oligomers can be incorporated into cleaning agents, polishes, paints, sprays, soaps, hand lotions or detergent formulations, as appropriate with suitable solvents (classes), carriers (classes), Thickeners, pigments, perfumes, deodorants, emulsifiers, surfactants, wetting agents, waxes or oil combinations. If the polymer or oligomer is used as a preservative in food, the polymer or oligomer can be added to the food as any edible medium or carrier that can also include a suitable medium or carrier for convenient mixing or dissolution in the food. A part of the formulation. The amount of polymer or oligomer added to or incorporated into a formulation such as a dressing, polishing, soap, or food is sufficient to kill the desired microbial species or inhibit the growth thereof, and can be readily determined by those skilled in the art. .

Regarding those applications in which the polymers and oligomers of the present invention are used as surface-mediated microbicides, for example, in some applications as anti-infective agents and as preservatives (eg, including but not limited to) Devices such as catheters, bandages, and implants, or food containers and food processing equipment that combine polymers and oligomers in a suitable manner (including covalent bonding, ionic interaction, Coulomb interaction, hydrogen bonding, or Cross-linking) is applied to or coated on almost any substrate, including but not limited to wood, paper, synthetic polymers (plastics), natural and synthetic fibers, natural or synthetic rubber, cloth, glass and ceramics. .

The steps of attaching, coating and incorporating the polymer of the present invention with an oligomer in an appropriate substance or matrix are disclosed in WIPO Publ. No. WO 02/072007, the disclosure of which is incorporated herein in its entirety by reference. Suitable matrices and materials are also disclosed in WO 02/072007.

The following examples are illustrative of, but not limited to, the methods and compositions of the present invention. Other suitable modifications and adaptations of the various conditions and parameters which are commonly encountered and understood by those skilled in the art are within the spirit and scope of the invention.

Example 1

Method for synthesizing benzynyl oligomers The following general methods can be used to synthesize benzynyl oligomers.

Starting with dibromobenzoic acid, the appropriate dibromide carboxylate monomer is converted to the corresponding cyanide and subsequently reduced to the amine. The dibromide is reacted with diethynylbenzene via Sonogashira to give the final trimer. Treatment of the amine with N,N'-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine followed by deprotection with Boc afforded the fluorenyl derivative. See, for example, Arnt, L. and Tew, GL, J. Am. Chem. Soc. 124:7664-7665 (2002), supporting data on experimental procedures and compound characteristics (see page 7665) (accessible from the Internet) Http://pubs.acs.org).

The benzynyl terpolymer 3 was synthesized according to this procedure as exemplified in FIG. Starting with dibromobenzoic acid, the dibromobenzoic acid monomer is converted to the corresponding cyanide and subsequently reduced to the amine (50% overall yield). The dibromide is then coupled to the diethynylbenzene via a Sonogashira coupling to give the final terpolymer with a 30% yield. Treatment of the amine with N,N'-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine followed by deprotection with Boc afforded the fluorenyl derivative.

Example 2

Antimicrobial activity of benzynyl oligomers The antimicrobial activity of the benzynyl trimer oligomer series in vitro and its selectivity to bacterial or mammalian cells was tested.

Antibacterial assays using a modified method of the standard micro-media dilution assay recommended by the American Committee for Clinical Laboratory Standards (NCCLS) have been developed to determine the antimicrobial activity of cationic agents in vitro (Liu, D. and DeGrado, WF, J. Amer. Chem. Soc. 123:7553-7559 (2001); Steinberg, DA et al. Antimicrob. Agents Chhemother. 41:1738-1742 (1997); Yan, H. and Hancock, REW, Antimicrob. Agents Chemother. 45:1558-1560 (2001); Amsterdam, D., "Susceptibility testing of antimicrobials in liquid media", in Antibiotics in Laboratory Medicine, 4 ^{t h} edition, Loman, V., ed., Williams and Wilkens, Baltimore, MD (1996), pp. 52-111). Modifications to minimize the loss of antimicrobial agents are due to adsorption on glass or plastic surfaces and precipitation at high concentrations. This step is the most rigorous test for antibacterial activity because of the high ionic strength of the growth medium, which inhibits the action of the cationic agent, but better reflects the activity of the human body. The optical density of the culture at 600 nm was measured on a microdisk reader to assess bacterial cell growth after incubation for 18 to 20 hours for each compound. The MIC (minimum inhibitory concentration) of each compound was determined.

The antimicrobial activity of the arylguanamine oligomer was designed, synthesized and tested using the procedure as described above. The hemolysis of human erythrocytes after 1 hour incubation in the presence of the oligomer to be tested was measured to determine the cytotoxic selectivity of the bacteria relative to mammalian cells (Liu, D. and DeGrado, WF, J. Amer. Chem. Soc . 123: 7553-7559 (2001)), and determining the IC ₅₀ oligomers. HC _{5 0} values represent the concentration causing 50% of oligomers of hemoglobin released.

The results are presented in Table 1.

The data in Tables 1 and 2 show that Compound 1 inhibits the growth of Gram-negative E. coli and Gram-positive Bacillus subtilis. The hydrophobicity at R1 is improved and the erythrocyte cytotoxicity is reduced to a lesser extent (Compound 2 and Compound 4). Further modification of the positive charge at R2 significantly reduced erythrocyte toxicity, while also improving potency, resulting in a highly potent and selective compound (having only molecular weight 595, compound 3). The bactericidal activity of Compound 3 against MBC of E. coli D31 (defined as a reduction of >3 logarithm by bacterial titration) was 0.8 μg/ml.

Compound 3 was then screened for growth inhibition (MIC) activity against Gram-negative bacterial kits. Gram-positive organic system bacilli, Listeria, and staphylococcus species included in the screening method. The results presented in Table 3 show that Compound 3 has broad-spectrum and effective activity against many, if not all, of the bacteria in the kit. Compound 3 effectively inhibits the growth of many important human pathogens (including Listeria, Pseudomonas aeruginosa, and Staphylococcus aureus) and also inhibits the growth of bacteria (Lactococcus and Salmonella) that generally have antimicrobial peptides. . Effective activity against B. subtilis and Bacillus cereus (ATCC 21929) It is considered that Compound 3 can also inhibit the growth of Bacillus anthracis which is mainly related to these three strains.

Example 3

Antibacterial activity of benzynyl oligomers against group A biopathogenic bacteria Bacillus anthracis, Tularensis bacillus and Yersinia pestis To measure the efficacy against effective biological weapon pathogens, the phenylalkynyl oligomerization of Example 2 above was determined. compound 3 was against Bacillus anthracis and Yersinia pestis MIC _{5 0 0} value.

Bacillus anthracis and plague cultures were established as follows: For plague cultures, blood agar plates were streaked in frozen plague bacteria tubes (YP.NM 4 stock solution) and at 37 ° C, 5% CO ₂ Cultivate for 48 hours. At the end of the second day, colonies from previously prepared blood agar plates were added to 10 ml of Mueller Hinton II medium (BBL, Becton Dickinson, #3338743 lot) and incubated overnight at 37 ° C, 5% CO ₂ . Establish small cultures. The mini cultures were diluted 1:10 and incubated for 3 hours at 37 ℃, 5% at CO _2, reaches until OD _{6 0 0} 0.115 (about 4x10 ⁷ cfu / ml) was far, large-scale cultures were established. The entire culture was then diluted to about 5x10 ⁵ cfu / ml, for assay use. For the B. anthracis culture, the blood agar plates were streaked in a frozen Bacillus anthracis tube (BA-NS-2 bacterial stock solution) and incubated overnight at 37 ° C, 5% CO ₂ . On the next morning, colonies from previously prepared blood agar plates were isolated in 10 ml of Mueller Hinton II medium (BBL, Becton Dickinson, #0327000 lot) and incubated at 37 ° C, 5% CO ₂ . Small cultures. At the end of the day, the previous culture was diluted 1:1000 in the medium and incubated overnight at 37 ° C, 5% CO ₂ to create a new mini-culture. The small culture was 1: 1000 dilution and the lower ₂ at 37 ℃, 5% CO incubated for 6 hours until the OD _{6 0 0} 0.3 (about 2x10 ⁶ cfu / mL) until the establishment of a large culture.

The MIC (minimum inhibitory concentration) was carried out in a 96 well plate using a two-fold dilution series of Compound 3 and a positive control agent (Seplo) (repeated). The source of the plague vaccination in the assay well was 4.1 x 105 cfu/ml and the B. anthracis inoculation source was 8 x ^{10 4} cfu/ml (total volume of 200 microliters). The assay disk was inserted into a bioscreen reader (Thermo Labsystems, Franklin, MA, USA) and incubated at 37 ° C, 5% CO ₂ . The final MIC values of Y. pestis and Bacillus anthracis were recorded at 30 hours and 24 hours, respectively (Table 4). MIC values shown represent the only organisms including control wells is observed the lowest concentration of each compound ≦ 10% of the OD _{6 0 0.}

In a secondary screen, Compound 3 against a variety of clinical/field isolates of Bacillus anthracis and Yersinia pestis was screened. The MIC assay was performed under conditions similar to those described above according to the NCCLS guidelines. In the 2% Iso Vitalex supplemented in Ca ^{2 + -} adjusted Mueller Hinton broth in test Tulare subtilis, and absorbance was read at 24 and 48 hours. Use Siplow as an antibiotic agent positive control and use S. aureus as a microbicide control. The MIC _{1 0 0} value represents the lowest concentration of the compound which is judged by turbidity and does not cause any growth in appearance.

In both sets of screens (Tables 4 and 5), Compound 3 was found to be effective and comparable growth inhibitory activity against all tested biological weapon pathogenic strains. 3 to measure the compound with respect to Staphylococcus aureus and Saipu Luo (Cipro) with respect to the expectations of the biological pathogens MIC _{1 0 0} values in the assay support integrity of the assay in parallel.

The MIC studies of Bacillus anthracis, as concluded in Table 4, were performed in an automated screening manner, and a total of 24 hours of organism growth was recorded at 2 hour intervals. Compound 3 exhibited complete growth inhibition at the early and late time points, consistent with rapid bactericidal activity (Fig. 3A). A completely different growth inhibition sequence was observed with the antibiotic Cipro positive control, with transient cell growth observed at the initial time point at MIC and 2xMMIC concentrations (Fig. 3B). Cipro is a bactericidal antibiotic that acts as an intracellular enzyme involved in DNA synthesis, which is the standard for the treatment of anthrax infection. These results show that Compound 3 exhibits a significant advantage over Cipro. An important requirement for an effective treatment for infection with Bacillus anthracis and other biological pathogens is to treat immediately after exposure and before the infection reaches the ineffective phase of antibiotic medical treatment (often before the onset of symptoms). Therefore, it is best to kill bacterial compounds quickly.

Example 4

Anti-bacterial activity of phenyl alkynyl oligomers against human pathogenic bacteria associated with nosocomial infections Compound 3 was screened for antibacterial activity against Escherichia coli, Staphylococcus aureus, and chloramphenicol-resistant Staphylococcus aureus (MRSA). The results are presented in Table 6.

Growth inhibition assays have been developed according to a modification of the standard micro-media dilution assay recommended by the American Committee for Clinical Laboratory Standards (NCCLS), which has been developed to determine the antimicrobial activity of cationic agents in vitro (Steinberg et al. Antimicrob. Agents) Chemother. 41:1738 (1997); Yan and Hancock, REW, Antimicrob. Agents Chemother. 45:1558-1560 (2001)). Modifications to minimize the loss of antimicrobial agents are due to adsorption on glass or plastic surfaces and precipitation at high concentrations. The bacterial strain from the agar plate was inoculated in 5 ml of DIFCO Mueller-Hinton broth and incubated at 37 ° C for 2 to 3 hours on a shaker platform (180 rpm). The suspension was diluted to approximately 4x10 ⁵ cfu / ml and seeded 96-well flat plate (96 [mu] l volume) in a polypropylene flat bottom (Costar). Prepare a stock solution of the compound in DMSO and apply a two-fold dilution of the compound in 0.01% acetic acid, 0.2% fetal bovine blood albumin in a polypropylene eppendorf tube and add to the flat plate (10) Microliter volume), obtained from 200 to 3.125 μg/ml for the final concentration range. The DMSO concentration in the assay is no more than 1%. All samples were repeated three times. One set of control wells only included medium with dilution buffer for testing sterility and providing blank absorbance readings. A vehicle control well (without any compound) containing a bacterial suspension with DMSO is also included. After incubation overnight (20 hours), measuring the optical density of the culture at 600 nm (OD _{6 0 0)} in the micro plate reader to assess cell growth. The MIC _{1 0 0} value represents the lowest concentration of the compound that did not cause any growth in appearance.

The results presented in Table 6 show that Compound 3 is more effective than amikacin (a broad-acting aminoglycoside) against the drug-sensitive Escherichia coli and Staphylococcus aureus strains, while Obamika is observed. Xin is superior to the drug-resistant Staphylococcus aureus activity. The MRSA system is currently the leading human pathogen of most hospital infections.

In a secondary screen (Table 7), Test Compound 3 was tested against the biosuppressive activity of clinical isolates (including drug sensitive strains) of Gram-positive and Gram-negative pathogenic bacteria that are often associated with nosocomial infections. In addition, clinical isolates of non-filamentous mold (yeast) Candida albicans were also tested. Three positive control antibiotics (levofloxacin, linezolid and vancomycin) and an antifungal agent (amphotericin) B were included in the screening to confirm the integrity of the assay. Growth conditions were achieved under the NCCLS conditions modified as described above for growth cultures with the following changes: 1) Streptococcus pneumoniae and Streptococcus pyogenes: Mueller Hinton + 2-5% lysed horse blood; 2) Haemophilus: Mueller Hinton + NAD + yeast Extract + hydroxyhemoglobin; and 3) Candida albicans: RPMI synthetic broth (GIBCO).

(mic=MIC _{1 0 0} ) The results presented in Table 7 show that Compound 3 proved to be effective and broad-spectrum against the antimicrobial activity of almost all tested strains, including all coagulation-negative-staphylococcus, anti-octacillin (OX -R) Staphylococcus aureus, anti-wan-mycin (VAN-R) Enterococcus faecalis, anti-penicillin (PEN-R) Streptococcus pneumoniae and non-filamentous mold (yeast) Candida albicans. Pseudomonas aeruginosa isolates against various multi-drug resistant drugs (MDR) with effective and moderate antimicrobial activity were observed. The discovery of the expected sensation results with all controlled antibiotics according to the NCCLS guidelines supports the integrity of the assay. Further, Compound 3 obtained for both normally expected in the previous assay test method controllability ATCC bacterial strains (Enterococcus faecalis ATCC 29212 and Streptococcus pneumoniae ATCC 49619) MIC _{1 0 0} value. The broad-spectrum activity of Compound 3 against Gram-positive and Gram-negative bacteria, anti-drug strains and yeast shows that the benzynyl compounds of the present invention can be the best antimicrobial agents for medical applications for general or topical applications.

Antibacterial. In order to experimentally measure the resistance (or lack of resistance) of the antimicrobial activity of the bacteria to the benzynyl oligomer, continuous passage of Staphylococcus aureus in the presence of a by-MIC (0.5x) concentration of Compound 3 . The MIC _{1 0 0} values of 17 consecutive pathways were measured at every 24 hour time point, and the compound concentration of each pathway was 0.5x previously measured by the MIC _{1 0 0} . Two fluoroquinolones (cypolo and norfloxacin), also set at a concentration of 0.5x, were included in the assay as positive controls. Bacteria including Staphylococcus aureus can easily develop resistance to these two antibiotics in this experimental example.

Resistance to both spirop and norfloxacin was readily observed in early pathways 3 or 4, and the increased MIC was 125 and 160 times, respectively, in pathway 16. No consistent increase in MIC with Compound 3 was observed throughout the course of the experiment, which showed that the bacteria were not effective in evading the antimicrobial action of the benzynyl group.

Example 5

Antibacterial activity of a benzynyl oligomer embedded in a methyl urethane film The antibacterial activity retention of a benzynyl oligomer after incorporation into a methyl urethane film was investigated. In order to control the manufacturing cost, in terms of material application, the preferred antibacterial polymer and oligomer form are polymers. However, the use of oligomers in this initial study yielded the most reliable data for determining the structure/activity relationship of benzynyl polymers.

The antibacterial activity retention of the benzynyl trimer compound 3 was tested after the oligomer was incorporated into the sheet of the polyurethane film. The results are illustrated in Figure 4.

Untreated glass flakes, untreated methyl urethane film, and polymethyl methacrylate film including antimicrobial oligomers were inserted into a bacterial (E. coli D31) culture grown at 37 ° C for 72 hours. . The film was swollen with a solvent including an antimicrobial compound and allowed to dry to obtain a methyl urethane derived from the compound 3. Compound 3 was infiltrated into the membrane during this process. At the end of the 62 hour incubation period, significant bacterial growth was readily observed on the surface of untreated glass and methyl urethane. However, a slight increase in growth was observed on the compound 3-polymethylcarbamate film, which showed that the oligomer retained its antibacterial activity upon incorporation into the surface of the plastic film.

Experiments were performed using Listeria instead of E. coli and the same results were observed.

Example 6

Antiviral Activity of Oligomers One or more oligomers of the present invention (e.g., benzynyl oligomeric compound 3) were synthesized as described above and tested for their ability to inhibit HIV replication in cell culture. Two viruses were used in the infection assay: NLHX or YU2, using CXCR4 or CCR5 as co-receptors, respectively. One day prior to the start of infection, U87/CD4/CCR5 or U87/CD4/CXCR4 cells were seeded at 3x10 ⁴ cells/well in a 48 well plate. The cell culture supernatant was removed and replaced with the individual pseudotype luciferase reporter virus or pseudotype luciferase reporter virus and oligomer at the indicated final concentration. About 16 hours after infection, the virus and compound are removed from the cells, the cells are rinsed and then the culture is filled. Three days after infection, the cells were lysed and assayed for luciferase activity. The results are presented as a percentage of the luciferase activity observed in the absence of the compound.

Example 7

The antifungal activity of oligomers is tested against a group of oligomers of the invention (e.g., one or more oligomers of the invention, such as benzynylene trimer compound 3) in a number of different mold populations. Sensitivity. Non-filamentous molds (yeast) and filamentous molds were tested and selected for screening for specific molds associated with various human infection patterns (Table 8). The antifungal activity of one or more oligomers is tested. An antifungal assay was performed to determine the minimum inhibitory concentration that caused complete inhibition of growth (MIC _{1 0 0} ). All growth assays were performed in a total volume of 1 ml and growth was assessed by turbidity assay. Other antifungal assay conditions are illustrated in Table 9.

Example 8

Antifungal activity of the benzynyl oligomer The MIC (minimum inhibitory concentration) and MFC of the compound 3 in the above Example 2 for each of the four molds (Aspergillus fumigatus, Penicillium, Chaetomium and Trichoderma) (Minimum moldicidal concentration) value. The MIC value of Compound 3 against the mold Candida albicans was also determined. The results are presented in Tables 10 and 11 below.

The MIC endpoints of Aspergillus fumigatus, Penicillium, Chaetomium and Trichoderma were determined according to the NCCLS guidelines currently defined for testing Aspergillus fumigatus (NCCLS M38-A, 2002). The MIC endpoint of the yeast species was determined according to the NCCLS guidelines currently defined for testing Candida albicans (NCCLS M27-A2, 2002). Amphoteric mold B as a positive control product is included in the screening method for Candida albicans.

All MIC tests were performed in 96 well microtiter plates using RPMI 1640 medium (with glutamine and no bicarbonate) as growth medium. Growth values were read at 35 ° C and at 48, 72 hours (and 96 hours for some slow growing mold species). Each of the investigated compounds was tested in the range of 11 replicate dilutions (eg, 128-0.12 μg/ml).

The MFC (Minimum Bactericidal Concentration) endpoint was calculated using a modification method that defined the NCCLS method used to test the minimum bactericidal concentration (MFC). Experiments to calculate MFC were performed only for those organisms that met the calculated MIC endpoint. MFC is defined as the concentration necessary to reduce the number of organisms that are at least 90% visible.

Example 9

The ability of polymers and oligomers to inhibit the anti-coagulation effect of low molecular weight heparin. A number of amphoteric polymers and oligomers of the invention are synthesized and tested for their ability to inhibit the anticoagulant effect of heparin. It is assumed that the heparin neutralization activity is closely related to the charge and charge distribution characteristics of the polymer and the oligomer, and more than the amount of hydrophobicity.

The clotting time of the activated plasma caused by the fixed heparin concentration was tested in the presence of increasing concentrations of each polymer or oligomer. Measurement of activated plasma in 1 unit (0.2 μg/ml) of heparin in the presence and absence of four polymer or oligomer concentrations (44.4 μg/ml, 4.4 μg/ml, 1.5 μg/ml and 0.4 μg/ml) The clotting time in the presence. Each polymer or oligomer was assayed four times and the mean clotting time was determined. Collect the response data.

The clotting time was determined using an activated partial thromboplastin time assay (coagulation assay). The assay was performed as follows: A plasma sample (0.1 ml) including heparin or heparin and a polymer or oligomer to be tested was pipetted into the test tube and incubated at 37 ° C for about 2 minutes. A recombinant cephalinex (phospholipid platelet substitute available from Bio/Data) was added to the plasma sample. The mixture was incubated at 37 ° C for about 5 minutes. A 25 mM calcium chloride solution preheated to 37 ° C was added to the mixture, and the clotting time was recorded using a fibrometer.

The antagonism of clotting time delay caused by low molecular weight heparin (LMWH) was also investigated. The clotting time of activated plasma in the presence of 4.6 μg/ml of LMWH was measured in the presence or absence of three polymer or oligomer concentrations (14.8 μg/ml, 1.5 μg/ml and 0.4 μg/ml). Collect the response data.

Testing of polymer and oligos in the presence of one or more polymer or oligomer concentrations, testing clotting time of LMWH induced in three different LMWH concentrations (LeoPharm, 1 μg/ml) in whole blood LMWH-antagonistic activity of the polymer. To determine the performance of assays in whole blood to consider medical applications, as these assays show whether the possible binding of hemoglobin to polymers or oligomers is a possible controversy to impact bioactivity in vivo. The assay was performed in a manner similar to the assay using activated plasma, and the administration data was collected.

Example 10

The ability of a benzynyl oligomer to inhibit the anticoagulant effect of low molecular weight heparin In order to assess the possibility of a benzynyl oligomer as a low molecular weight heparin (LMWH) antagonist, assay compound 3 includes anti-LMWH Lovinos ( Lovenox) The ability to inhibit factor Xa (FXa) activity to determine compound 3. Briefly, FXa activity in the presence of Lovinos and inhibitors was measured using a chromogen assay using reagents available from DiaPPharma. The reagents were reconstituted in 0.02 M Tris buffer at pH = 8.4, and the final assay conditions were: 0.004 IU/ml AT, 0.14 nkat/well FXa, 0.01 M Tris, 0.15 M NaCl, 112 microliters final volume. Schild-plot analysis in order to establish the assay (for determination of K _b), different concentration of AT Lowe North incubated for 5 minutes. Different inhibitor concentrations were added to each well to construct a fixed inhibitory concentration profile and gently shaken and incubated for 20 minutes. Then FXa was added and the reaction was shaken and incubated for 10 minutes. Substrate (S-2765) was then added, causing a condensation ladder, and then the 96 well plate was shaken and read every 30 seconds at 405 nm on a ThermoLabsystems Multiskan Spectrum for 7 minutes. Lowe North single curved titration experiments (determination of IC _{5 0)} lines of the same steps, but at a fixed concentration Lowe North (in the absence of inhibitors as measured). Each curve analysis was performed using GraphPad Prism version 4.0 of Windows.

Effective antagonism Compound 3 on Lowe North inhibiting factor Xa activity (IC _{5 0} = 5.07μM) phenyl alkynyl support the present invention as antagonists LMWH medical use.

The present invention is now fully described, and it is to be understood by those skilled in the art that the present invention may be practiced in the broad and equivalent conditions, the compositions, and other parameters, without departing from the scope of the invention or any specific embodiments thereof.

All documents cited herein are hereby incorporated by reference in their entirety for the same extent as the extent of the disclosure of the disclosures Patent publication. When the cited document only provides the first page of the document, it intends to quote the entire file, including the remaining pages of the file.

Figure 1 shows a schematic representation of the structure of the cationic and amphoteric alpha-helical host defensive peptides (Memanning 1). The hydrophobic residue is dark and the basic residue is light.

Figure 2 illustrates a synthetic representation of the synthesis of the benzynyl trimer compound 3.

Figure 3 shows the results of the growth inhibition schedule test described in Example 3, in which Compound 3 was tested for its ability to inhibit Bacillus anthracis over time. Figure 3A represents the data obtained with Compound 3. Figure 3B represents data obtained with the positive control of the antibiotic ciprofloxacin.

Figure 4 shows the results of a assay in which a benzynylene trimer compound 3 is incorporated into a methyl urethane film. The figure represents untreated glass (top), untreated methyl urethane film (middle) and methyl urethane film containing compound 3 (bottom), which is present in E. coli The graphs after 62 hours of incubation were each.

Claims (9)

An oligomer of the formula Ia or a pharmaceutically acceptable salt thereof, R ¹ -A ₁ -sA ₂ -sA ₁ -R ² (Ia) wherein: A ₁ and A ₂ are independently m-phenylene, wherein A ₁ is substituted by one polar (PL) group, and A ₂ is unsubstituted; s is -C≡C-; R ¹ is bromine or iodine; R ² is R ¹ ; PL is selected from the group consisting of Group of polar groups: fluorenylmethyl, decylethyl, aminomethyl, aminoethyl and aminoethylamine carbonyl. The oligomer according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A _{1 is} further substituted with a non-polar (NPL) group, wherein the NPL is a n-pentyloxy group. An oligomer according to claim 1 or a pharmaceutically acceptable salt thereof, which is one of the following . A pharmaceutical composition comprising the oligomer of any one of claims 1 to 3 and a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition for treating a microbial infection, comprising the oligomer of any one of claims 1 to 3, and a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition according to claim 5, wherein the microbial infection is a bacterial infection, a mold infection or a viral infection. A pharmaceutical composition for killing or inhibiting the growth of a microorganism, which comprises the oligomer of any one of claims 1 to 3 and a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition according to item 7 of the patent application, wherein the microorganism is a bacterial cell, a mold or a virus. A pharmaceutical composition for administering an antidote to a low molecular weight heparin in an overdose, comprising the oligomer of any one of claims 1 to 3 and a pharmaceutically acceptable carrier or diluent.